CA3206012A1

CA3206012A1 - Compounds for rna capping and uses thereof

Info

Publication number: CA3206012A1
Application number: CA3206012A
Authority: CA
Inventors: Jiancun Zhang; Lijun Zhang; Yiqian ZHOU; Jiafeng Chen; Jufu ZHANG; Suyong LI; Yanhui LIU; Chen Guo; Wanjun TANG; Feng Wu; Xiaoxi HE; Qi Guo; Huixuan CHEN; Kun Wang; Deyao LI
Original assignee: Guangzhou Henovcom Bioscience Co Ltd
Current assignee: Guangzhou Henovcom Bioscience Co Ltd
Priority date: 2022-02-28
Filing date: 2022-09-22
Publication date: 2023-08-28
Also published as: KR20230173077A; EP4261217A1; EP4261217A4; JP7642260B2; JP2024532025A; EP4261217A9; AU2022430003B9; US12060385B2; KR102750248B1; AU2022430003B2; US20230340009A1; AU2022430003A1

Abstract

The present invention relates to compounds for RNA capping and uses thereof, which belong to the technical field of genetic engineering. Compounds of formula I can result in high levels of capping efficiency, and the capped mRNA exhibits increased expression.

Description

COMPOUNDS FOR RNA CAPPING AND USES THEREOF
FIELD OF TECHNOLOGY
The present invention relates to the technical field of genetic engineering, and particularly, it relates to compounds for RNA capping and uses thereof.
BACKGROUND
The five-prime cap (m7GpppN) structure of mRNA was discovered in 1970s, and its presence provides stability for mRNA and enables its efficient translation. There are usually three types of cap structures (m7G5'ppp5'Np, m7G5'ppp5'NmpNp, m7G5'ppp5'NmpNmpNp), named Type 0 (m7G5'ppp5'Np), Type 1 (m7G5'ppp5'NmpNp), and Type 2 (m7G5'ppp5'NmpNmpNp), respectively. Type 0 has an unmethylated ribose in the first nucleotide at the terminus, Type 1 has a methylated ribose in the first nucleotide at the terminus, Type 2 has a methylated ribose in both nucleotides at the terminus.
In eukaryote, in addition to recognizing the initiation of protein synthesis, the 5'-cap structure also functions as a protective group from 5' to 3' exonuclease cleavage, i.e., it is resistant to 5'- exonuclease degradation. It also serves as a unique identifier for recruiting protein factors for pre-RNA splicing, polyadenylation and nuclear export during protein synthesis, and acts as an anchor for recruitment of initiation factors, which helps the ribosome to recognize and bind mRNAs for proper translation initiation.
Studies have shown that the cap structure of mRNA is importantly linked to RNA
quality control and intrinsic immunity of the organism, and therefore, it is important to provide a system that can improve the capping efficiency, and can increase the mRNA expression after capping.
SUMMARY
Based on this, it is necessary to address the above problem and provide a compound for RNA capping.
When the compound is used for capping 5' ends of mRNA, it can result in high levels of capping efficiency and the capped mRNA exhibits increased expression.
It is one object of the present invention to provide a compound of formula I, or a stereoisomer, or a pharmaceutically acceptable salt, or a solvate thereof:

Date Recue/Date Received 2023-07-07 R'\
+N=\ R9 \ Y
0 N..._ ,,, X3 ,. ....y3 __ a N 7 x4, T Y-P-Y -P-YchP-Yd HN , N XI; Xa / Y2a Y2b / Y2c : -) W 4 \x, m1 z1 oR3a _ \

\

- Hd bR3b- m2 I
wherein:
R' is Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkene, benzyl, R5-substituted C1-C6 alkyl, Rs-substituted C2-C6 alkenyl, Rs-substituted C2-C6 alkynyl, Rs-substituted C3-C6 cycloalkyl, Rs-substituted C3-C6 cycloalkene, or Rs-substituted benzyl;
Xa is 0, S, Se, CH, CHCN, CHN3, or NRio; or when Xa is 0, 5, Se, CHCN, CHN3, or NRio, XI, X2, and R2 are absent;
Xb is 0, 5, Se, C, or -NRio; or when Xb is 0, 5, Se, or NRio, W and R1 are absent;
X1 is absent, or X1 is (CH2)., or NR4;
X2 is absent, or X2 is 0,5, NR4, CO, CO2, CONR4, NR4CO, NR4CO2, NR4CONR4, SO2, SO2NR4, or CH2;
X3 is 0,5, NR4, CH2, CF2, CHF, CCH2, or CCF2;
X4 is 0, 5, CH2, NR4, or NCOR4; or -X4-, in each instance, is a single bond or a double bond; or when -X4-, in each instance, is a double bond, W is absent;
R is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, cycloalkene, benzyl, aryl, heteroaryl, R5-substituted benzyl, Rs-substituted aryl, carbonylakl, carbonylalkoxy, or sulfanilamido;
R1 is absent, or R1 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Rs-substituted C1-C6 alkyl, R5-substituted C2-C6 alkenyl, Rs-substituted C2-C6 alkynyl, or halogen;
R2 is NRs, or ORs; or R2 is absent, or R2 is H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, Rs-substituted C1-C8 alkyl, R5-substituted C2-C8 alkenyl, Rs-substituted C2-C8 alkynyl, aryl, Rs-substituted aryl, heteroaryl, Rs-substituted heteroaryl, halogen, CN, or N3;

2 Date Recue/Date Received 2023-07-07 each of R3a and R3b is absent; or each of R3a and R3b is independently selected from H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Rs-substituted C1-C6 alkyl, Rs-substituted C2-C6 alkenyl, or Rs-substituted C2-C6 alkynyl;
W is absent, or W is H, 0,011, OR4, NR4R4, NR4COR4, F, Cl, N3, or CN; or R1 and W are connected to form a ring by chemical bonds; or W and X2, or W and R2, or W and R9, or R9 and X2 are connected to form a ring by chemical bonds; and each of a, - b V V, - Vc, and Yd is independently selected from 0, 5, CH2, CC12, CF2, or NH;
-each of V
- la, - V lb, and Yic is independently selected from 0, or 5;
each of V
- 2a, - V 2b, and Y2c is independently selected from OH, SH, or BH3;
each of Y3 and Y4, is independently selected from CH2, or 0;
Z1 is 0,011, CH2, 5, NR6, CO, or SO2;
each of Z2 and Z3 is absent, or each of Z2 and Z3 is independently selected from 0, NR6, CHR7, CHCOOR7, CHCONR7R7, 5, CO, SO2, P0(011), P0(511), or P(0)VCO2H; or Z2 forms a ring with oxygen atom linked to R3a;
Z4 is absent, or Z4 is 0, CH2, 5, NR6, CO, or SO2;
each of Bi and B2 is independently selected from natural or modified pyrimidine base, or natural or modified purine base;
R4 is H, CI-Ca alkyl, C2-C8 alkenyl, or C2-C8 alkynyl;
R5 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, OR7, SR7, NR7R7, COR7, COOR7, OCOOR7, CONR7R7, NHCOR7, OCONR7R7, halogen, CN, 502, NO2, D, N3, aryl, or heteroaryl;
R6 is H, C1-C6 alkyl, COR8, or 502R8;
R2 is absent, or R2 is H, CI-Ca alkyl, C2-C8 alkenyl, or C2-C8 alkynyl;
R8 is H, C1-C8 alkyl, C2-C8 alkenyl, or C2-C8 alkynyl;
R9 is H, C1-C3 alkyl, or R4-substituted C1-C3 alkyl; or when -X4- , in each instance, is a single bond, R9 and W are connected to form a ring by chemical bonds, or R9 and X2 are connected to form a ring by chemical bonds;
R10 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, benzyl, aryl, COR8, CO2R8, CONR8R8, or 502R8;
V is C1-C4 alkyl;
mi is 1, 2, or 3;

3 Date Recue/Date Received 2023-07-07 m2 is 0, 1, or 2; and n is 1, 2, or 3.
In some examples, X1 is absent, or X1 is (CH2)11, or NR4, X2 is 0,5, CO, CO2, CONR4, NR4CO, NR4CO2, NR4CONR4, 502, or SO2NR4; and R2 is H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, Rs-substituted C1-C8 alkyl, Rs-substituted C2-C8 alkenyl, Rs-substituted C2-C8 alkynyl, aryl, Rs-substituted aryl, heteroaryl, Rs-substituted heteroaryl, or CN.
In some examples, R5 is C1-C4 alkyl, C2-05 alkenyl, C2-05 alkynyl, C1-C4 haloalkyl, C2-05 haloalkenyl, C2-05 haloalkynyl, OR7, SR7, NR7R7, COR7, COOR7, OCOOR7, CONR7R7,NHCOR7, OCONR7R7, halogen, CN, SO2, NO2, D, N3, aryl, or heteroaryl; and R2 is H, C1-C4 alkyl, C1-C4 alkenyl, or C1-C4 alkynyl.
In some examples, Z1 is CH2, or NR6.
In some examples, R6 is H, C1-C4 alkyl, COR8, or 502R8;
RS is H, C1-4 alkyl, C2-05 alkenyl, or C2-5 alkynyl.
In some examples, X1 is absent, or X4 is (CH2)11, or NR4;
X2 is absent, or X2 is 0, 5, CO, CONR4, NR4CO, NR4CO2, or NR4CONR4;
when X3 is present, X3 is 0;
X4 is absent, or X4 is 0, or NCOR4; or -X4-, in each instance, is a single bond or a double bond; or when -X4-, in each instance, is a double bond, W is absent;
R is H;
R1 is absent, or R1 is H, or halogen;
R2 is absent, or R2 is C 1-C8 alkyl, C2-C8 alkenyl, Rs-substitutued C2-C8 alkyl, Rs-substitutued aryl, heteroaryl, or N3;
when R3a and R3b are present, each of R3a and R3b is H;
W is 0, or OH;
each of Ya, Yb, Y, and Yd is independently selected from 0, or CH2;
each of V
- la, - V lb, and Yic is independently selected from 0, or 5;
each of V
- 2a, - V 2b, and Y2c is independently OH;
each of Y3 and Y4 is independently selected from CH2, or 0;
Zi is 0,011, CH2, 5, or NR6;
each of Z2 and Z3 is independently selected from 0, NR6, CHR7, CHCOOR7, CO, SO2, or P0(011);

4 Date Recue/Date Received 2023-07-07 when Z4 is present, Z4 is 0, or C112;
or when Zi is 0, Z2 is P0(011); or when Z3 is 0, X1 is absent; or when -X4-, in each instance, is a single bond, X2 is not 0; or when m2 is 0, Zi is OH; and when X is absent and -X4-, in each instance, is a single bond, X2 is not 0;
and each of Bi and B2 is independently selected from natural or modified pyrimidine base, or natural or modified purine base;
R4 is H, or C1-C8 alkyl;
R5 is OR2, NR2R2, CONR2R2, OCONR2R2, or halogen;
R6 is H;
R2 is H, or C1-C8 alkyl;
when R10 is present, R10 is H, or C1-C3 alkyl;
mi is 1;
m2 is 0, or 1; and n is 1, or 2.
In some examples, X1 is absent, or X1 is (012)11;
X2 is 0;
when X3 is present, X3 is 0;
when X4 is present, -X4-, in each instance, is a single bond;
R is H;
when R1 is present, R1 is H;
R2 is CI-CS alkyl, or Rs-substituted Ci-C8 alkyl;
when R3a and R3b are present, each of R3a and R3b is H;
W is OH;
each of Ya, Yb, Ya , and Yd is independently selected from 0, or CH2;
each of V
- la, - V lb, and Yia is independently selected from 0, or S;
each of V
- 2a, - V 2b, and Y2a is independently OH;
each of Y3 and Y4 is independently CH2;
Zi is 0, OH, or NR6;
each of Z2 and Z3 is independently 0, CHR7, or PO(OH);
when Z4 is present, Z4 is CH2;
Date Recue/Date Received 2023-07-07 or when Z1 is 0, Z2 is P0(011); or Z3 is 0, X1 is absent; or when -X4-, in each instance, is a single bond, X2 is not 0; or when m2 is 0, Z1 is OH; and when X1 is absent and -X4-, in each instance, is single bond, X2 is not 0;
and each of Bi and B2 is independently selected from natural or modified pyrimidine base, or natural or modified purine base;
R5 is aryl;
R6 is H;
R7 is H;
when R9 is present, R9 is H;
mi is 1;
m2 is 0, or 1; and n is 1.
More preferably, when X2 is absent, or X2 is S. or N, R2 is C1-C4 alkyl, C2-C6 alkenyl, C1-C4 haloalkyl, C2-C6 haloalkenyl, CN, N3, or morpholine.
In some examples, when X2 is absent, or X2 is 5, R2 is methyl, ethyl, propyl, halomethyl, haloethyl, halopropyl, CN, N3, or morpholine.
In some examples, the compound has a structure of formula IV-A shown as follows:
R' + N=\ R9 0 N X3 t--Y3 Yla Y1 b Y1 c Ya-P-Y
H N N Y2a Y2b Y2c WR4 (CH2)n M1 Zi 0R3, R-NH

Z4 ..cc_7B 2 . _ Hd OR3b IV-A
wherein, X2 is absent, or X2 is not CH2; or when X2 is present, X2 is 0, 5, NR4, CO, CO2, CONR4, NR4CO, NR4CO2, NR4CONR4, SO2, or SO2NR4.
In some examples, the compound has a structure of formula IV shown as follows:

Date Recue/Date Received 2023-07-07 R'\
+N=\ R9 sz Y1 a Y1 b Y1 c 0 N N.,5 HN, r ,N Y_2a ''2bb Y2c wRi .. (cH2), mi zi 0R3a R_NH \z2 Z4 Ct),B2 . _ Hd -OR3b IV
wherein, X2 is absent, or X2 is not CH2; or when X2 is present, X2 is 0, 5, NR4, CO, CO2, CONR4, NR4CO, NR4CO2, NR4CONR4, 502, or SO2NR4.
In some examples, R1 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Rs-substituted C1-C6 alkyl, R5-substituted C2-C6 alkenyl, Rs-substituted C2-C6 alkynyl, or halogen;
W is H, 0,011, OR4, NR4R4, NR4COR4, F, Cl, N3, or CN;
R4 is H, C1-C8 alkyl, C2-C8 alkenyl, or C2-C8 alkynyl;
R5 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, OR7, SR7, NR7R7, COR7, COOR7, OCOOR7, CONR7R7, NHCOR7, OCONR7R7, halogen, CN, 502, NO2, D, N3, aryl, or heteroaryl;
R7 is absent, or R7 is H, C1-C8 alkyl, C2-C8 alkenyl, or C2-C8 alkynyl; and ml is 1, or 2.
In some examples, when R1 is H, W is H, OH, OR4, NR4R4, NR4COR4, F, Cl, N3, or CN;
R4 is H, C1-C4 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl.
Preferably, when R1 is H, W is H, OH, OR4, NR4R4, F, Cl, or CN; and R4 is C1-C4 alkyl.
More preferably, when R1 is H, W is OH, F, Cl, methoxy, trifluoromethoxy, ethoxy, or trifluoroethoxy.
In some examples, the compound has a structure of formula IV-1 shown as follows:

Date Recue/Date Received 2023-07-07 R' + N=\
0 Y1a Y1b Y1c N N = , ya y yc H y !Y4 o Bi I I
H N N
Y2a Y2b Y2c W (CH2), m 1 Zi b R3a R - N H

z/3 Z4,.c0iB2 Hd b R3b IV-1;
wherein, R' is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkene, benzyl, Rs-substituted C1-C6 alkyl, Rs-substituted C2-C6 alkenyl, Rs-substituted C2-C6 alkynyl, Rs-substituted C3-C6 cycloalkyl, Rs-substituted C3-C6 cycloalkene, or Rs-substituted benzyl;
R is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, cycloalkene, benzyl, aryl, heteroaryl, R5-substituted benzyl, Rs-substituted aryl, carbonylakl, carbonylalkoxy, or sulfanilamido;
R2 is absent, or R2 is H, CI-Ca alkyl, C2-C8 alkenyl, C2-C8 alkynyl, Rs-substituted Ci-C8 alkyl, R5-substituted C2-C8 alkenyl, Rs-substituted C2-C8 alkynyl, aryl, Rs-substituted aryl, heteroaryl, Rs-substituted heteroaryl, halogen, CN, or N3;
each of R3a and R3b is independently selected from H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, substituted C1-C6 alkyl, Rs-substituted C2-C6 alkenyl, or Rs-substituted C2-C6 alkynyl;
W is H, OH, OR4, NR4R4, F, Cl, or CN;
each of Ya, Yb, Y, and Yd is independently selected from 0, S. CH2, CC12, CF2, or NH;
each of V
- la, - V lb, and )(la is independently selected from 0, or S;
each of V
- 2a, - V 2b, and Y2a is independently selected from OH, SH, or BH3;
each of Y3 and Y4 is independently selected from CH2, or 0;
Zi is 0,011, CH2, S, NR6, CO, or SO2;
each of Z2 and Z3 is absent, or each of Z2 and Z3 is independently selected from 0, NR6, CHR7, CHCOOR7, CHCONR7R7, 5, CO, SO2, P0(011), PO(SH), or P(0)VCO2H;
Z4 is absent, or Z4 is 0, CH2, 5, NR6, CO, or SO2;
each of B1 and B2 is independently selected from naturalor modified pyrimidine base, or natural or modified purine base;
R4 is H, C1-C8 alkyl, C2-C8 alkenyl, or C2-C8 alkynyl;

Date Recue/Date Received 2023-07-07 R5 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, OR7, SR7, NR7R7, COR7, COOR7, OCOOR7, CONR7R7, NHCOR7, OCONR7R7, halogen, CN, 502, NO2, D, N3, aryl, or heteroaryl;
R6 is H, C1-C6 alkyl, COR8, or 502R8;
R7 is H, C1-C8 alkyl, C2-C8 alkenyl, or C2-C8 alkynyl;
R8 is H, C i-C8 alkyl, C2-C8 alkenyl, or C2-C8 alkynyl;
V is C1-C4 alkyl;
mi is 1, or 2; and n is 1, 2, or 3.
In some examples, the compound has a structure of formula IV-2 shown as follows:
R'\
+N=\
Y y 0 m 0 v Y,,la I=Ilb lc 0 N - 3 -Ya-P-Y -P-Y,HP-Yd HN
Y2a Y2b Y2c W (CH2), nil Z1 b R3a R-NH
\z2 ZiOiB2 Hd -OR3b IV -2;
wherein, R' is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkene, benzyl, Rs-substituted C1-C6 alkyl, Rs-substituted C2-C6 alkenyl, Rs-substituted C2-C6 alkynyl, Rs-substituted C3-C6 cycloalkyl, Rs-substituted C3-C6 cycloalkene, or Rs-substituted benzyl;
R is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, cycloalkene, benzyl, aryl, heteroaryl, R5-substituted benzyl, Rs-substituted aryl, carbonylakl, carbonylalkoxy, or sulfanilamido;
R2 is absent, or R2 is H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, Rs-substituted C1-C8 alkyl, R5-substituted C2-C8 alkenyl, Rs-substituted C2-C8 alkynyl, aryl, Rs-substituted aryl, heteroaryl, Rs-substituted heteroaryl, halogen, CN, or N3;
each of R3a and R3b is independently selected from H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, R5-substituted C1-C6 alkyl, Rs-substituted C2-C6 alkenyl, or Rs-substituted C2-C6 alkynyl;
W is H, OH, OR4, NR4R4, F, Cl, or CN;
each of Ya, Yb, Y, and Yd is independently selected from 0, 5, CH2, CC12, CF2, or NH;
each of V
- la, - V lb, and )(la is independently selected from 0, or 5;

Date Recue/Date Received 2023-07-07 each of V
- 2a, - V 2b, and Y2c is independently selected from OH, SH, or BH3;
each of Y3 and Y4 is independently selected from CH2, or 0;
Z1 is 0,011, CH2, 5, NR6, CO, or SO2;
each of Z2 and Z3 is absent, or each of Z2 and Z3 is independently selected from 0, NR6, CHR7, CHCOOR7, CHCONR7R7, 5, CO, SO2, P0(011), P0(511), or P(0)VCO2H;
Z4 is absent, or Z4 is 0, CH2, 5, NR6, CO, or SO2;
each of B1 and B2 is independently selected from natural or modified pyrimidine base, or natural or modified purine base;
R4 is H, C1-C8 alkyl, C2-C8 alkenyl, or C2-C8 alkynyl;
R5 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, OR7, SR7, NR7R7, COR7, COOR7, OCOOR7, CONR7R7, NHCOR7, OCONR7R7, halogen, CN, 502, NO2, D, N3, aryl, or heteroaryl;
R6 is H, Ci-C6 alkyl, COR8, or 502R8;
R2 is H, C1-C8 alkyl, C2-C8 alkenyl, or C2-C8 alkynyl;
R8 is H, C1-C8 alkyl, C2-C8 alkenyl, or C2-C8 alkynyl;
V is C1-C4 alkyl;
mi is 1, or 2; and n is 1, 2, or 3.
In some examples, the compound has a structure of formula IV-3 shown as follows:
R' +N=\
y y 0 m 0 y Y,,la = lb lc hP-Yd HN N Y2a Y2b Y2c .
W (CH2), m 1 Zi 0R3, R-NH \z2 Hd oR3b IV -3;
wherein, R' is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkene, benzyl, Rs-substituted C1-C6 alkyl, Rs-substituted C2-C6 alkenyl, Rs-substituted C2-C6 alkynyl, Rs-substituted C3-C6 cycloalkyl, Rs-substituted C3-C6 cycloalkene, or Rs-substituted benzyl;
Date Recue/Date Received 2023-07-07 R is H, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, cycloalkene, benzyl, aryl, heteroaryl, R5-substituted benzyl, Rs-substituted aryl, carbonylakl, carbonylalkoxy, or sulfanilamido;
R2 is absent, or R2 is H, C i-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, Rs-substituted Ci-C8 alkyl, R5-substituted C2-C8 alkenyl, Rs-substituted C2-C8 alkynyl, aryl, Rs-substituted aryl, heteroaryl, Rs-substituted heteroaryl, halogen, CN, or N3; or R2 is NRs, or OR5;
each of R3a and R3b is independently selected from H, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, R5-substituted C1-C6 alkyl, Rs-substituted C2-C6 alkenyl, or Rs-substituted C2-C6 alkynyl;
W is H, OH, OR4, NR4R4, F, Cl, or CN;
each of Ya, Yb, Y, and Yd is independently selected from 0, 5, CH2, CC12, CF2, or NH;
each of V
- la, - V lb, and Via is independently selected from 0, or 5;
each of V
- 2a, - V 2b, and Y2a is independently selected from OH, SH, or BH3;
each of Y3 and Y4 is independently selected from CH2, or 0;
Z1 is 0,011, CH2, 5, NR6, CO, or SO2;
each of Z2 and Z3 is absent, or each of Z2 and Z3 is independently selected from 0, NR6, CHR7, CHCOOR7, CHCONR7R7, 5, CO, SO2, P0(011), P0(511), or P(0)VCO2H;
Z4 is absent, or Z4 is 0, CH2, 5, NR6, CO, or SO2;
each of Bi and B2 is independently selected from natural or modified pyrimidine base, or natural or modified purine base;
R4 is H, C1-C8 alkyl, C2-C8 alkenyl, or C2-C8 alkynyl;
R5 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, OR7, SR7, NR7R7, COR7, COOR7, OCOOR7, CONR7R7, NHCOR7, OCONR7R7, halogen, CN, 502, NO2, D, N3, aryl, or heteroaryl;
R6 is H, Ci-C6 alkyl, COR8, or S02R8;
R2 is H, C1-C8 alkyl, C2-C8 alkenyl, or C2-C8 alkynyl;
R8 is H, C1-C8 alkyl, C2-C8 alkenyl, or C2-C8 alkynyl;
V is Ci-C4 alkyl;
mi is 1, or 2; and n is 1, 2, or 3.
In some examples, the compound has a structure of formula IV-4 shown as follows:

Date Recue/Date Received 2023-07-07 R' + N=\
Y y 0 Yla = lb lc N N 0Y3 y yc y 0 B1 H N N Y2a Y2b 1Y2c W (CH2)n m 1 Z OR3a R - N H _ R4 ¨N. .0 Z2 -S' Z4,c0_72 Hd aR3n 11-12 IV -4;
wherein, R' is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkene, benzyl, Rs-substituted Ci-C6 alkyl, Rs-substituted C2-C6 alkenyl, Rs-substituted C2-C6 alkynyl, Rs-substituted C3-C6 cycloalkyl, Rs-substituted C3-C6 cycloalkene, or Rs-substituted benzyl;
R is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, cycloalkene, benzyl, aryl, heteroaryl, R5-substituted benzyl, Rs-substituted aryl, carbonylakl, carbonylalkoxy, or sulfanilamido;
R2 is absent, or R2 is H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, Rs-substituted C1-C8 alkyl, R5-substituted C2-C8 alkenyl, Rs-substituted C2-C8 alkynyl, aryl, Rs-substituted aryl, heteroaryl, Rs-substituted heteroaryl, halogen, CN, or N3;
each of R3a and R3b is absent, or each of R3a and R3b is independently selected from H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Rs-substituted C1-C6 alkyl, Rs-substituted C2-C6 alkenyl, or Rs-substituted C2-C6 alkynyl;
W is H, 0,011, OR4, NR4R4, NR4COR4, F, Cl, N3, or CN;
each of Ya, Yb, Y, and Yd is independently selected from 0, S. CH2, CC12, CF2, or NH;
each of V
- la, - V lb, and )(la is independently selected from 0, or S;
each of V
- 2a, - V 2b, and Y2a is independently selected from OH, SH, or BH3;
each of Y3, and Y4 is independently selected from CH2, or 0;
Z1 is 0,011, CH2, 5, NR6, CO, or SO2;
each of Z2 and Z3 is absent, or each of Z2 and Z3 is independently selected from 0, NR6, CHR7, CHCOOR7, CHCONR7R7, 5, CO, SO2, PO(OH), PO(SH), or P(0)VCO2H; or Z2 forms a ring with oxygen atom linked to R3a, Z4 is absent, or Z4 is 0, CH2, 5, NR6, CO, or SO2;

Date Recue/Date Received 2023-07-07 each of Bi and B2 is independently selected from natural or modified pyrimidine base, or natural or modified purine base;
R4 is H, CI-Ca alkyl, C2-C8 alkenyl, or C2-C8 alkynyl;
R5 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, OR7, SR7, NR7R7, COR7, COOR7, OCOOR7, CONR7R7, NHCOR7, OCONR7R7, halogen, CN, 502, NO2, D, N3, aryl, or heteroaryl;
R6 is H, C1-C6 alkyl, COR8, or 502R8;
R2 is absent, or R2 is H, C1-C8 alkyl, C2-C8 alkenyl, or C2-C8 alkynyl;
R8 is H, C1-C8 alkyl, C2-C8 alkenyl, or C2-C8 alkynyl;
V is C1-C4 alkyl;
mi is 1, 2, or 3;
m2 is 0, 1, or 2; and n is 1, 2, or 3.
In some examples, the compound has a structure of formula VI-5 shown as follows:
R' + N=\
0 m 0 y Yla Ylb Ylc N 3 Ya -P-Yc HN N Y2a Y2b Y2c W (CH2), M1 Zi b R3a R-NH \z2 R4 -N.

0' R2 Z4,,c0iB2 Hd -OR3b VI-5;
wherein mi is 1, or 2.
In some examples, the compound has a structure of formula VI -6 shown as follows:
R'\
+ N=\
0 m 0 v Yla Ylb Ylc N 3 -Ya-P-Y -P-Yc P-Yd HN N Y2a Y2b Y2c W (CH2)n m1 Z1 b R3a R -N H \z2 HN, Z4,..c0iB

Hd OR3b Date Recue/Date Received 2023-07-07 VI -6;
wherein, R' is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkene, benzyl, Rs-substituted C1-C6 alkyl, Rs-substituted C2-C6 alkenyl, Rs-substituted C2-C6 alkynyl, Rs-substituted C3-C6 cycloalkyl, Rs-substituted C3-C6 cycloalkene, or Rs-substituted benzyl;
R is H, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, cycloalkene, benzyl, aryl, heteroaryl, R5-substituted benzyl, Rs-substituted aryl, carbonylakl, carbonylalkoxy, or sulfanilamido;
R2 is absent, or R2 is H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, Rs-substituted C1-C8 alkyl, R5-substituted C2-C8 alkenyl, Rs-substituted C2-C8 alkynyl, aryl, Rs-substituted aryl, heteroaryl, Rs-substituted heteroaryl, halogen, CN, or N3;
each of R3a and R3b is absent, or each of R3a and R3b is independently selected from H, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Rs-substituted C1-C6 alkyl, Rs-substituted C2-C6 alkenyl, or Rs-substituted C2-C6 alkynyl;
W is H, 0,011, OR4, NR4R4, NR4COR4, F, Cl, N3, or CN;
each of Ya, Yb, Y, and Yd is independently selected from 0, S. CH2, CC12, CF2, or NH;
each of V
- la, - V lb, and Via is independently selected from 0, or S;
each of V
- 2a, - V 2b, and Y2a is independently selected from OH, SH, or BH3;
each of Y3, and Y4 is independently selected from CH2, or 0;
Zi is 0,011, CH2, S, NR6, CO, or SO2;
each of Z2 and Z3 is absent, or each of Z2 and Z3 is independently selected from 0, NR6, CHR7, CHCOOR7, CHCONR7R7, S. CO, SO2, PO(OH), PO(SH), or P(0)VCO2H; or Z2 forms a ring with oxygen atom linked to R3a;
Z4 is absent, or Z4 is 0, CH2, 5, NR6, CO, or S02;
each of Bi and H2 is independently selected from natural or modified pyrimidine base, or natural or modified purine base;
R4 is H, C1-C8 alkyl, C2-C8 alkenyl, or C2-C8 alkynyl;
R5 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, OR7, SR7, NR7R7, COR7, COOR7, OCOOR7, CONR7R7, NHCOR7, OCONR7R7, halogen, CN, SO2, NO2, D, N3, aryl, or heteroaryl;
R6 is H, C1-C6 alkyl, COR8, or 502R8;
R2 is absent, or R2 is H, C1-C8 alkyl, C2-C8 alkenyl, or C2-C8 alkynyl;
R8 is H, C1-C8 alkyl, C2-C8 alkenyl, or C2-C8 alkynyl;

Date Recue/Date Received 2023-07-07 V is C1-C4 alkyl;
mi is 1, 2, or 3;
m2 is 0, 1, or 2; and n is 1, 2, or 3.
In some examples, R4 is H, C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl;
RS is Cl-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, OR7, SR7,NR7R7, COR7, COOR7, OCOOR7, CONR7R7, NIIC0R7, OCONR7R7, halogen, CN, 502, NO2, D, N3, aryl, or heteroaryl;
R6 is H, C1-C4 alkyl, CORs, or 502R8;
R7 is H, C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl; and R8 is H, C1-C4 alkyl, C2-05 alkenyl, or C2-05 alkynyl.
In some examples, Z1 is 0, C112, 5, or NH;
each of Z2 and Z3 is absent, or each of Z2 and Z3 is independently selected from NR6, CHR7, CHCOOR7, CHCONR7R7, 5, CO, SO2, P0(011), or PO(SH);
Z4 is absent, or Z4 is 0, C112, 5, or NH;
each of Bi and B2 is independently selected from natural or modified cytosine base, natural or modified uracil base, natural or modified adenine base, or natural or modified guanine base;
R6 is H, methyl, ethyl, propyl, or isopropyl; and R7 is H, methyl, ethyl, propyl, or isopropyl.
In some examples, each of Ya, Yb, Y, and Yd is 0, or at most one of Ya, Yb, Y., and Yd is 5, C112, CCi2, CF2, or N11;
each of V
- la, - V lb, and Yiõ is 0, or at most one of Yla, Ylb, or Y1 c is 5;
each of V
- 2a, - V 2b, and Y2c is OH, or at most one of Y- 2a, Y2b, or Y2c is SH, or BH3;
each of Y3 and Y4 is independently CH2;
Z2 is absent, or Z2 is CH2, CH2CH2, CO, SO2, or P0(011);
Z3 is 0, CH2, or NH; and Z4 is CH2, or NH.
More preferably, each of Ya and Yd is 0, or at most one of Ya and Yd is 5, or CH2.
More preferably, each of Yb and Yc is 0, or at most one of Yb and Yc is 5, CH2, CC12, CF2, or NH.
More preferably, Z2 is CH2, SO2, or P0(011).
In some examples, W is H, OH, OR4, NR4R4, F, Cl, or CN;
Date Recue/Date Received 2023-07-07 R' is Ci-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkene, benzyl, Ci-C4 haloalkyl, C2-C4 haloalkenyl, C2-C4 haloalkynyl, C3-C6 halocycloalkyl, C3-C6 halocycloalkene, or halobenzyl;
R is H, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkene, C1-C4 haloalkyl, C2-C4 haloalkenyl, C2-C4 haloalkynyl, C3-C6 halocycloalkyl, C3-C6 halocycloalkene, benzyl, or halobenzyl;
R2 is absent, or R2 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Rs-substituted Ci-C6 alkyl, R5-substituted C2-C6 alkenyl, Rs-substituted C2-C6 alkynyl, aryl, Rs-substituted aryl, heteroaryl, Rs-substituted heteroaryl, halogen, CN, or N3;
each of R3a and R3b is independently selected from H, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C2-C4 haloalkenyl, or C2-C4 haloalkynyl;
R4 is H, methyl, ethyl, n-propyl, isopropyl, butyl, ethenyl, propenyl, butenyl, ethynyl, propynyl, or butynyl;
R5 is Cl-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, OR7, SR7, NR7R7, COR7, COOR7, halogen, CN, D, N3, pyridine, pyrimidine, or morpholine; and R7 is H, methyl, ethyl, n-propyl, isopropyl, butyl, ethenyl, propenyl, butenyl, ethynyl, propynyl, or butynyl.
In some examples, W is OH, F, Cl, methoxy, or ethoxy.
More preferably, W is OH, or methoxy.
In some examples, each of R3a and R3b is independently H, methyl, ethyl, n-propyl, isopropyl, propenyl, propynyl, halomethyl, haloethyl, halopropyl, or haloisopropyl.
More preferably, each of R3a and R3b is independently H, methyl, ethyl, n-propyl, isopropyl, propenyl, propynyl, fluoromethy 1, difluoromethyl, trifluoromethyl, trifluoroethyl, trifluoropropyl, or trifluoroisopropyl.
More preferably, each of R3a and R3b is independently H, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, or trifluoroethyl.
In some examples, R' is methyl, ethyl, n-propyl, isopropyl, butyl, ethenyl, propenyl, butenyl, ethynyl, propynyl, butynyl, benzyl, halomethyl, haloethyl, halopropyl, haloisopropyl, halobutyl, haloethenyl, halopropenyl, halobutenyl, haloethynyl, halopropynyl, halobutynyl, or halobenzyl.

Date Recue/Date Received 2023-07-07 More preferably, R' is methyl, ethyl, n-propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, trifluoropropyl, trifluoroisopropyl, benzyl, p-fluorobenzyl, p-chlorobenzyl, difluorobenzyl, or dichlorobenzyl.
More preferably, R' is methyl, ethyl, n-propyl, isopropyl, difluoromethyl, trifluoromethyl, trifluoroethyl, trifluoropropyl, or trifluoroisopropyl.
More preferably, R' is methyl, ethyl, n-propyl, isopropyl, difluoromethyl, trifluoromethyl, or trifluoroethyl.
In some examples, R is H, methyl, ethyl, n-propyl, isopropyl, butyl, ethenyl, propenyl, butenyl, ethynyl, propynyl, butynyl, benzyl, halomethyl, haloethyl, halopropyl, haloisopropyl, halobutyl, haloethenyl, halopropenyl, halobutenyl, haloethynyl, halopropynyl, halobutynyl, or halobenzyl.
More preferably, R is methyl, ethyl, n-propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, trifluoropropyl, or trifluoroisopropyl.
More preferably, R is methyl, ethyl, n-propyl, isopropyl, difluoromethyl, trifluoromethyl, or trifluoroethyl.
In some examples, R2 is H, methyl, ethyl, n-propyl, isopropyl, butyl, hexyl, ethenyl, propenyl, butenyl, ethynyl, propynyl, butynyl, benzyl, halomethyl, haloethyl, halopropyl, haloisopropyl, halobutyl, halohexyl, haloethenyl, halopropenyl, halobutenyl, haloethynyl, halopropynyl, halobutynyl, halobenzyl, halogen, C1-C4 pyridinylalkyl, Ci-C4 pyrimidinylakl, Ci-C4 alkoxy-C1-C4 alkyl, Ci-C4 amidoalkyl, or Ci-C4 alkylamio-C1-C4 alkyl.
In some examples, R2 is H, methyl, ethyl, n-propyl, isopropyl, butyl, ethenyl, propenyl, butenyl, ethynyl, propynyl, butynyl, benzyl, halomethyl, haloethyl, halopropyl, haloisopropyl, halobutyl, haloethenyl, halopropenyl, halobutenyl, haloethynyl, halopropynyl, halobutynyl, halobenzyl, pyridinylmethyl, py ridiny 'ethyl, pyrimidiny 'methyl, pyrimidiny 'ethyl, methoxymethyl, ethoxymethyl, ethoxyethyl, amidomethyl, or methylaminomethyl.
In some examples, R2 is H, methyl, ethyl, n-propyl, isopropyl, butyl, propenyl, butenyl, propynyl, butynyl, difluoromethly, trifluoromethyl, difluoroethyl, trifluoroethyl, benzyl, F, Cl, methoxymethyl, ethoxymethyl, ethoxyethyl, amidomethyl, or methylaminomethyl.
In some examples, R2 is H, methyl, ethyl, n-propyl, isopropyl, butyl, propenyl, butenyl, propynyl, difluoromethly, trifluoromethyl, trifluoroethyl, benzyl, methoxymethyl, ethoxymethyl, or ethoxyethyl.
In some examples, the compound is selected from any one of the following compounds:

Date Recue/Date Received 2023-07-07 \ \

0 0 0 /--,N
toYy N.'50___''''0 Hi N OH O H OH - == N HN,N OH OH OH ,' , N ---.
N
.1- HO d oMe ----' -,-- HO 0 OMe "---' 0, 0, /
H2N Me0 'P, H2N
, OH 0 N--- d OH

r-._N
¨:(1,\I--õõ(õ0 OH
N bvi .,..õ(NH HO' - N-, NH
I

Compound 3 Compound 4 \
\ -,N= N NH2 0 0 0 \

\ OPOPOPONC =/ HN N N OH OH OH ' -- -- -, N
N
HN, _N OH OH OH T Ho d 'OMe -----' r HO q ,o 'OMe H2N AcHN 0, /
H2N P __N
OMe 0/ OH
N / NH
\,..___5....N, .0 N=K
I 'f' NH2 HO' - NI, NH
OH .Y.

Compound 5 Compound 6 o 0 N N NH
It7-,1 \
->N
o 0 0 0 N N NH2 4 N=\
0 0 0 0 , N N

0Ycil.'oi 0YY ' ='0 P o I= o I= 0'...cit OH OH OH OH OH OH
HO
6 /0 bMe r HO
6 ,0 OMe H2N l'' N 0 H2N K ,,..J\I 0 \.....,01,NI / NH
----'01 N=----( 0 NH2 N=---( . .

Compound 16 Compound 17 o \
0 0 .
, No N H2 0 0 . N N NH2 ON''. ..µµO P 0 P 0 P 0 i HN ,N
-,--- HO OH OH OH : -- Ome N , N
HN .__N OH OH OH 0' 0 t)Me H2N 0 Nr HO

H2N F, OMe 0 0 6 OH -;j_lit-- (:) \*...õ.r ....0 0 h / NH \_--NH
6, ,...õ N=-( .\------/
HO
NH2 ' - 0 OH
HO' '0H
Compound 18 Compound 21 o No \ N
ONo o o o 0 N / NH
N''' POPOPO N=( -,N=\

n N N NH2 HN .---NN OH OH OH -......--C¨r NH2 C'Y'Y 5_/ OPOPOP0'.--CY
odsH):0:1-1bM6e\H-F F
6 ,0 OMe HN,..,N OH OH OH
H2N Me0 P,' N r HO
NH

\,.....,(01 / NH 0.--01' N=(\õ.....c0IN / NH
NH2 N=( Hd :OH
Compound 22 Compound 23 Date Recue/Date Received 2023-07-07 \N 0 \ \-____ +N=\
0 \-3R74 0 0 0 0 0y N=_( (DN.'' '''Cr-CP-0-0P-0-0P-0'....N / NH
N=( ON''' õN OH OH OH , -, NH2 HNN OH OH OH .' f HO 0 OMe r HO 0 OMe H2N 0 _7-0H N

H2N \
o o ¨NH
µN,--N _( i NH
¨ \N.-\ N
\ NH2 \ NH2 HO OH
HO OH
Compound 29 Compound 30 o \ N N
-N1=\
0 0 0 4 \ 1,--7, N / NH
OYYN "n'''0 P 0 P 0 P 0"...---ey.cl.Z N NH2 N
HN-N OH OH OH ,_,,, -, N=--( o''''CrIsiAµo 0 Pr 0 0'...
f He) 0, MO e NH2 HNõN OH OH OH
d OH \-- 2- , 0 sK ___NI 0 T HO o, /0 OMe NH H2N 0 F' N=_( 0 /1,1==(NH
\ NH2 NH
Hb. OH
HO' OH
Compound 31 Compound 32 \
+1,1=\
+1,1=\
0 0 0 u N N 0 0 0 0 N N NH2 HNõry OH OH OH ,- , HNN OH OH OH
A 2- -, T HO 0, ,0 OMe r HO 0, o am.
H2N 0 lz, N 0 H2N 0 F,' _._tki C) H
\.... c.1 N
N= H---( 0\
N=---( HO' i":)H 1-1,E 6H
Compound 33 Compound 34 o o N/-NH
0.,,yN,,, 0 ..,,,0 0 ij,r NIANH
\
o I NNH2 \
oN 1 NNH2 +N=\
+N=\

orq.''k(D
OH OH OH -= -- HNN OH OH OH , r HO d, /0 OMe f HO Cis ,0 Orme H2N o F, 6\.....OH
NC----X d OH NNH H2N 0 Hr \ K _.., j \I

\-NH \....õc0IN /
0 N=-( õ
HO OH Hd -OH
Compound 35 Compound 36 N) NH
\ 7 \
o N 1 ,,J
+N=\
o.N=\N ,,,,,,õ0 , 0 , 0 , 0 N N NH2 N NH2 0 0 0 0 0 Ha 11Flo ilFle) ilc3F10,---.
HN,_,N
( i 0, zo OMe r HO q ,o Om.
r_NH o P. N1 0 H2N N3 N 0 -,--"-I \ 6 OH (T___ \,......cy / NH 6 OH 44 õ,._0_! / NH
N=--( N=--( HO OH HO OH
Compound 37 Compound 38 Date Recue/Date Received 2023-07-07 N N
litX
\ 111:,111,-1 \
*N 0 N N NH2 + N=\

(:)-II -olLo-iLo's-Li `31\i C) '1" 0 A 0 A 0 A 0'-..--00/
HN- N OH OH OH ,,. =/ HN ,,...N OH OH OH
I HO Os ,0 bme 'Tee HO ds ,0 bme H2N 0 K N1 H2N T K 1\1 0 'CF, d OH \ "" CP, d OH \ \ N__ 4 \,...../)v / NH
N=( N=( NH2 _\ NH2 --/, Hd Ohl HO' OH
Compound 39 Compound 40 \ \
+ N1=\ D D D o F¨N
oYNI111 11" I

õ I 0y,,,yN.õ d ,.,1-,,oi120 ILL Cr N0 V
HN , N OH OH OH HN , N OH OH OH )""K
Ny,y , NH
HO
d bmeNyNH
-r- HO 0, O 0Me y H2N HN ' P,OH 0/ NH2 H2N HN 'P, OH NH2 /o 6 0 \ /=N H2N ...,coy. ,...,coi.... /=N
N,,f0 N
HO' ' N , NH N yl\IH
bH y OH

Compound 47 Compound 48 \ \
N=\ /=N

(:)---CrIsl.' C) r\l Y'" '"'o A o A o A o N NH2 N HN õ, N O H OH OH '7¨K N N
"7" HO b,o Me Nr- HO 0, , d Ome H2N ¨N 'P, H2N 'P, \ 6 OH C:1 0/ OH
\o_.. F¨N

H011 -/oH NyNH
OH N yNH

Compound 49 Compound 50 \ \
/=N

YYN111 0 11µµ 0 01A 0 01A 0 01A 0'...--10--.N V NH2 YY+Ni=\N111 111µ0 0 0 0'...--O--.NNV i OH OH OH HN ,...N OH OH OH = - N N
1Nr/1"- HO
0, /
d 'O H2N
).---- HO
d bme H20 -P, H2N ..--..õ./..-""
0111-1-' d OH 0 0/ OH
coi_..
No NO
HO' ' OH N OH ---, NH HO' ' N ---, NH
y y Compound 51 Compound 52 \ \
+ N=\
NO /= + N=\
0 0 0 /=N1 O 0N.,, O ,õ, 11 11 11 o y),..õ.....r,NH
y-Y"." 01= o :)I= o :)I= 's-10-." 2 H OH OH - " bme N , N
HO 0 di -- HN --N' HO N 0 H OH OH d-. ,bmeN N
-r- , /
H2N , C), ' P. , H2N 0 0 0 d OH
C) d OH
c3 /=N NH2 N
co__y...
NO
y),y0 HO' ' N , NH HO' / N yNH
OH y OH

Compound 53 Compound 54 Date Recue/Date Received 2023-07-07 \
\ + N=\ /=N
+ N=\

0 0 0 0 0 /=0 N

(7)/N ' '5N NH2 '. N''' 0 P 0 P 0 P
0'.....""0"... 1 i OH OH OH
HN ,.... N - .- N -, N
HN N OH OH OH - ' N , N 0,1=r,d 6 M e '''1--- HO cL
'OMe -- Nr-- HO 1 H2N `P, H2N ...,.N.,., 0 ----.N..: H
\==,,,0 \ _... /=N
--- N N yk,r0 N 0 /
,L--/¨

HO" - N , NH HO' '-_. NH
oH y OH NY

Compound 55 Compound 57 \ \
+ N=\
0 0 0 0 /N 0 , 0 0 0 /=N

0 0 P 0 P 0 P 0'......-0... oY''Y+Ni=\5 (:)-P-O-P-O-P-CINN?`y i 61-I 6H OH == -- I
HN ,... N
HN ,.- N OH OH OH - ' N , N 0' ome N N
-T--- HO ome ----- -7-- HO /S
HO- ' P, H2N ...,,,õØ., 'P, H2N F3C

H
Ny.,...y N 0 HO' ' OH N OH , NH HO' ' N , NH
y y Compound 58 Compound 92 \
+ N=\
0 0 0 0 F=N

õ,., NH2 O---NI'''0'.."--0-"Nr (3-:-Yr\i''' ''0 (:)1I, 0 0II) 0 0II4 0 OH OH OH --, N , N HN, -N OH OH OH d.
-f- HO OMe ---"" 1-- HO
HO ' HO-F,' H2N -P, H2N
N3 0/ -o CN 0/ '0 ,. .
HO' ' N -, NH HO' - N . NH
OH y OH y Compound 93 Compound 95 CI
P , 0 0 . 0 /=N 13''',. N.' HN 0 oy,y"=\N=., ..00 01g 0 <j (D
i ig 0 g 0,====-Ø.. ,N OH OH OH N N
HN,2.õ-- HO o N OH OH OH -= .- ' --r- HO 0µ' --ome--HO ' T ' bme N N H2N -P, HO- ' OMe d -0 H2N P.
\
OMe d''' c0". T=NI
HO' " OH N ,... NH
y HO' ' N -, NH
bH y NH2 Compound 98 Compound 100 \ \
+N=\

0 0 0 0 0 /=N
Oy ,.--cr,N.,, .,, 11 11 11 ,,,,y,,r NH2 ''''0 p 0 p 0 p 0"..-..s.C1'NNH2 (j'.Yr\i''' ''''''OPOPOPON

OH OH OH ="- N N HN N
--,--- HO _ 0. bMe -,--- HO OH OH OH _=-bMeN , N
H2N Me0 O-P, H2N 0-d '0 OMe 0/ '0 IT-NH
HO' 'OH 0 HO' 'OH 0 Compound 110 Compound 111 Date Recue/Date Received 2023-07-07 \ \
+N=\

/=--N
ON.., ..,-,0 A 0 A 0 A 0 NNH2 OyzN. 0 .,õ 9 0 010100-------0---NNH, I II
HN ,N OH OH OH HNN OH OH OH 0,,' , y HO _ d bme N N NN N
H2N 0 0-- H2N AcHN 0 .-F;
NMe2 0/ ' 6 coi...Nr---c) NH
1_3....r\r"c) )- y-NH
HO' 61-1 0 HO ' 0 OH
Compound 117 Compound 118 \ \
+N=\
0 0 0 r=1\I +N=\

o 3...NrNH2 NyõT,NH2 OH OH OH -. I HNN OH OH 1-1 ' I
- , T HO _ o' bme N N T HO 0' 'omeN
N ----...--H2N 0-F; H2N o--p', IN-) d OMe d ).rNH
H0µ -.:_ 0 Ho' OH
Compound o oh! -Compound 119 Compound 121 \ \
+N=\
0 0 0 0 /=N\ +N=\
0 /=N
OyN''' CI ''O-P ..--0--.Nri NH2 tjy,õy ',, 01glg01g_cr^.--0... N
HN ,...N OH H H _ -bMeNN HN bme , HO N OH OH BH
,"- N N
y O O
HO
y S' H2N o-F; H2N
ome d ome 0) ).-NH Ir-NH
HO' uhl "2, o HO'u .,;,1-1 0 Compound 122 Compound 125 \
\ ,,, 0 õoioLoi (:' N=\
0 0 0 ,, (:) /=N N NH
..,,,, II II II --C i ,.---+ c , o 01,_01, ./...laNy)--õTrN112 HNõ __-N OH OH OH -- N , N
HN _....--N OH OH OH
,r HO 0,,,d_ bMe ----"
HO _ d bme H2N Bn0 F, H2N O-P, OMe 0 Ni=Nr\I 0 ' , HO' -bH a HO' -0H N NH1-Compound 128 Compound 135 \

C),I\l''' oAoAoi=
O 0"Nr7 i a Ny,,,c,HH2 CP 0 13 0 I3 0 I HN ,...N OH OH OH : -- N N
OH
OH OH : -. N, N --r-- HO d b Me r HO b me ----' 0, /
OP /d H2N HO
H2N Bn0 0 , 0 \...õCOyNi¨N0 rNH
HO' ' N,NH
õL----(_ O

H

Compound 136 Compound 137 Date Recue/Date Received 2023-07-07 \
O 0 0 + N=\

i NH2 0 N,, 0 i= NN H2 fjYYNI'' 0II' 0 II' 0 II
HO bme 0 HN --N OH OH OH
HN , N OH OH OH - = N , N Nre HO d bme --' --r- d . /
H2N Et0 H2N HO 6 o / o c(Dy.r\
NH 1_3....N 0 , y-HO' -6 HO' H 0 'OH y Compound 138 Compound 139 \
\ 0 0 0 =N--=\ F=N
+ N=\ /=N

N N, o , 1, 1, 1, 0 NH2 OyN,, 0 .,,(:) IV, 0 IV, 0 (:),,, 0,....0,0 NN?(NH2 CDPOPOPO
Z , OH OH OH - '= N , N 1-17kr,,,,,N 5-- OH OH OH
'......Q.NN, N
r HO ci 'OMe --' = T HO d bme 0., , H2N 0 H2N Et0 'P,- , 0 6 o \µµ...3.... /-_=N

r\r OMe Nykr.0 yNH
HO N NH
HO' ' bH0 'OH i Compound 140 Compound 141 \

+N=\
0 0 0 i=1\1 N NH2 = -0-Ls.rN,R,µ d OMe 11 11 11 -''' O y-i, ThDPOPOPONY'yNH2 HN.õ2,,..--N OH OH OH
d ,c)meNI, N
OH OH OH 7 HO ) -,---- HO -' HN 0 , 0 _..r\ N17,ep ...' OMe , rNH
HO' N NH
HO' " 0 OH ----/' '01-1 Compound 142 Compound 143 \
0 0 0 /=N
-, N=\
0 0 0 /=N N 7 0 0 OYYl\l'. ' ,C) II" 0 II" 0 II" 0 N'' ''',0 A 0 A 0 "
p 0....--0...NNE12 HNN 6H 6H OH iN
HT ,-.4':'N1.1'.: OH OH OH : - N N HO
-,--- HO
O. /
d bme'"'-=
H2N F3C0 0,,,,/!_ bMe N

/=
..,,r 0 ... Nrr Ne )NH
HO' OH 0 '()H HO' ' N., NH

Compound 144 Compound 145 \

(:) /=N NH2 0 0 0 Y'YN'"µ
o 0 0.
OH OH OH
HO
OH OH OH - OMe NN N N Nr-- HOR 0 OMe NN
= r 0, H2N 0 0. /

6 o ---y N?je HO' ' N , NH
HO' " 0 /,D1-1 y bH

Compound 146 Compound 147 Date Recue/Date Received 2023-07-07 \
O 0 0 0 il_ 0 N , NH2 I:)' 0 I:)' 0 01I' 0 HN , N OH OH OH
HO d bme r 1 : -= N ,, N HN N OH OH OH : --N , N
r HO d bme -,--- o. /
H
H2N 0 2N o 6 o o c_0_y=Nr-\ NO ,o Ne-f N.,_17, NH
HO'L----{43- H
HO' " 0 Compound 148 Compound 149 \
(:)N,,, 0 (II II D 0 01, 0 Oii, 0,....Ø...0 NNr NH2 0 N

N''. 1:') 0 ": 0 l?' 0,.....Ø..?õ,cr7 HN , N OH OH OH : , N , N HN , HO N O H OH OH -- --N , N
-,--- 6. bme ---' y o HO d bme 0- /
. / H2N o -P,-H2N o -P,- / 0 6 o \=õc0"..N/=0 HO' i:/1-1 N NH
" , " HO' y bH0 NH2 Compound 150 Compound 151 \
-,N=\ /=N ON, 0 9 9 9 ON,,.,,,,,õ 9 9 9 õ..-...._O,N,(NE12 OPOPOPOYyNH2 0 p-0-1.-0-1. 0 7 1 HN -- N O H OH OHNN
HN , N OH OH OH-, N )--- HO d bme -----' y o HO d bme -----' o. /
. / H2N
H2N o / 0 0 Nr-----ej NH N ¨N
HO' ' N NH
HO' " 0 bH y bH

Compound 152 Compound 153 \
0 0 0 0 in N,i17NH2 HN ,- N OH OH OH 0 ' 1 HN , _-- N OH OH OH
r HO 0 OMe --,--- HO d bme '--o, / H2N

OH 6 0 OEt 0 0 i=i\j =77--NH
HO' ' N ., NH
HO' " 0 OH 1 bH

Compound 154 Compound 155 \
\ -,N1=\ /=N
. N=\

0 I=N1 NH2 'ir N
, 0 õ , ii ii ii /--- 0 Fi'010 ol.NH2 (:)N" '' OPOPOPOY'lr HN , N OH OH OH : -= N , N HN ,... N OH OH OH -- -= N -õ N
)--- HO d oMe y HO Ci 'OM
0, / H2N
H2N 'P,- / 0 OEt 6 o c_Oi_..Nir\r- 0 i=N
Ne rNH
HO'. =-ip H N
NH
HO' -.6H 0 Compound 156 Compound 157 Date Recue/Date Received 2023-07-07 \
\ + NI=\
O 0 0 o /=I\1 r\l 0 N N,, 0 ,,, II II II N
0 (21, ' OPOPOPO N?rNH2 O'I= =I'lp A 0 A 0 A 0'-..--0-. ?.'`-rNH2 O O OH
I HN H H ,... N -- -= N , N
OH OH OH õ HO
-i--- HO d bme '--' o. /
o, / H2N

ocF, ocF2H O 0 /=I\1 \.....r,0y.14e õTr NH Z
HO' " 'OH 0 HO'. 'OH ' N , NH
y Compound 158 Compound 159 \
+N= =\ /=N 0, i N,, 0 1 0 , 0 ..õ, I`) ItII I
) 00 0 0 0 17 0 1 0 -.. NN?NH2 HN ,-- N OH OH OH ei: ,bme N õ N
HN ,- N OH OH OH : -= N , N ,,--- HO
'7"-- HO d bme -----' o, /
o, / H2N

o OCF, 6 o o ---c \..10"..NTIO
, r NH
bH Cr 'OH HO' "
N.,--T. ,NH

Compound 160 Compound 161 \
\ +N=\

0y.-y,.. 0 II II ii CIYYN'I. 0 =I'O-P-0-1L0-1L0'....s0'' HN, ___- N OH OH OH I
-- =- N , N HN ,N
HO Nr- OH OH OH -- , N , N
d'me ---"-T HO d bme ---H2N o 60 o o' ----\Toy r-\r )1-NH 1) 0 ril HO' ' N , NH
HO' --,_, uhl OH i Compound 162 Compound 163 \

Nykr,NH2 0 0 0 0 0 Or\i''. 0 ..'''oAoAoAo'---0--*

OYY''' 'ri 1 1 1 "" i OH OH OH : -= N , N HN ,-- N
0 --,--- HO OH OH OH ,:
%., O N , N
Me 'T-- HO d bme ----7 o, /
o, / H2N

a ¨r-Nro N
0 i=i\j H
...'"Ii...N n -Ho' ' N , NH
HO' "OH 0 'OH 1 Compound 164 Compound 165 \
+N=\ i=1\1 0 0 0 0 0 0 N,,NH2 NH
0 Ny7,\--õõr, 2 (314'.. ''''0 11' 0 11: 0 11' 0 I HN,, ,N OH OH OH -' -- N , N
T
HNN OH OH OH -: % NI, N r HO Ci bme --/ HO 0, p bme H2N o O
o 6 o \....õco___.... /-_N
Nyõtoo kr-Nr HO
HO' ' 0 bH 0 \ ' - N.,NH
01-1 --( Compound 166 Compound 167 Date Recue/Date Received 2023-07-07 \

P 0'2.2-c_0". 7 1 C)YYNNN?rNH, HN, _N 1 1 1 OH OH OHNN
HN, ,-- N OH OH OH - N
N , N
HT HO d o Me ---"' T HO = 6 'ome -- o.

H2N OBn 6 o o O ,--N
r\rr xir NH
, \ HO' ' o bH HO oH N NH--r Compound 168 Compound 169 \
o 0 H 0 0 0 H ..2 II II N NH2 y_crN,, 01: C
,:',,, 0 ,,, 0,0_,NyhrNH2 . P O POPO
7 i HNI-eiY,N .-- OH OH OH ---...---C):' I
HN,N OH OH OH , - N , N )--- HO d -bme'N
''"' T HO = ci bme -----"' o, /

OBn _0 NI=N

co_y_.,,,-r--\r I___> " c, \IT-NH
HO' ' N , NH
HO' -OH bH I

Compound 170 Compound 171 \

0 H 0 CI ..-, 11 11 2 II
e).-'-eY 5__ OPOPC 0_)-Ne\2'-ri Ci N" "µO P C2 P 0 P 0 N NH2 "
, N
) HN ,-N OH OH OH HN-N
OH OH OH
r HO 0- .-0 MeN
'-' --- HO = 0 bme ---' o, /
H2N Me0 H2N Me0 / 0 d 0 ¨N
Nr----N NH eD \--coy.c),f,, NO
.7r.
HO' ' N._ õ, NH
HO' ' 0 bH -1-Compound 172 Compound 173 \ \
+ N=\
0 0 ki 0 i=N +N=\
02 0 0 r=isl = ILO4-C'.2-VO
N,i)NH2 0y,,,,y, \,0,7 0 il, 0 il, 0 il, 0õ....Nyõ.,,cõNH2 I
' I HN, _., O N 1 1 1 H OH OH
0õ1 , N, N
HN , N OH OH OH - , N , N T HOi---) d ome -----HO d OMe ---z O. /
H2N Me0 H2N Me0 6 o i_Oi...Nr0 \r oh!
, \IT-NH
N -...,(NH
HO' " 0 Compound 174 Compound 175 \
+N=\ /=N 0 0 a 0 0 Cl2 0 ON, 0 "'0 P
0 P C 2 P 0'.....-0-..Nri NH2 'pr\j' = P C P 0 P 0 i HN, _.--- N OH OH OH
HN ,....N OH OH OH , - N , N r HO d bMe ----7 y HO d bm H2N Me e "-' 0,p/ _ 0. /
H2N Me0 0 ¨N
\=.õ , _v_i__O N/¨Nro ro .11..._ NH
HO' ' N , NH
HO' " 0 OH y OH

Compound 176 Compound 177 Date Recue/Date Received 2023-07-07 \
\ +N=\
S 0 0 /=--N
+1\1=\Oy--/-,,,r,N, \..,0,2 H NNH2 0,.1..õ__4,,y, Nõ 0 cj-0--bc12--0 0 NNH2 '" OPOPOPO 7 1 HN ,- N OH OH OH 1 - = N -.. N HN ..-= N
-7- HO OH OH OH ", N ---, N
d bMe '7"-- Ho d bme --' o.
o- / H2N Me0 \ 6 ,=N
H2N MO o o ¨N =.,, _0 \...õ.c0y.Nr-C) 0 rNH
HO N --, NH
HO, % 0 ON --r OH

Compound 178 Compound 179 \

N N' 1"OPOPOP S 0 0 O.
1 H , ,..1\ OH OH OH - =
HNI-1 OH OH OH - = N --, N 1 -r- HR d bmeN N
"--' y HO d bMe "---1-0, / H2N Mee H2N Me0 / 0 6 o NN?..,e r NH
HO' ' N , NH
'OH Cr 'OH i Compound 180 Compound 181 \

0 A 0 9 0 A 0N Yr7 i OY---YN" 00'-....-NY\----rNH2 HN,N OH OH OH N
OH OH OH T HO d bme '111( HO d 'me --- o. /
H2N Me0 H2N Me0 / 6 o 0 o o /="
.õ\,,o....Nr"-Nir NH
HO' - N ---iNH
HO' - 0 bl-1 bH

Compound 182 Compound 183 \
\
+ N=\ /=N + N=\

0 0 S 0N,,,õ. ii H ii ii 0 Ni=N

OYYNI'1 0 1"01'z'Ol'O II
PO N ).õ;\ --õ1õ NH2 N
OPNPOPOTe 1 HN -- N OH OH OH -, , N --,,N
OH OH OH - = N N )--11- HO 0 OMe HO 6 bme --' o. / H2N Me0 H2N Me0 rN
c) TO

r NH
HO' 1"-avl bH N-17-1-HO' Compound 184 Compound 185 \
\ + N=\
0 0 0 i=N
+ N=\
0 0 0 0 /=NI NH2 C)I\j'1 oAoAEN'Ao N , (:),yN1 0 1" 0 AIRIP,OP,o^0--Nr71 -- i HN õ. N OH OH OH - =
N -,. N
OH OH OH : = N -, N '11r- HO
y HO d bMe '1-'1-0, / H2N Me0 0,p/0_ bme '--' H2N Me0 / 0 NO

,r-NH
HO' ' N NH
HO' -- OH0 OH ---r Compound 186 Compound 187 Date Recue/Date Received 2023-07-07 \ =,1,1=\

HN ,--N OH OH OH -= N, N HN,_õ..-N
T HO' ) OH OH OH OH = - N., N
d bme o- , H2N Me0 H2N MO d0 \*....o..0 N c, ,r)t rNH
HO
HO' " 0 OH -7'e bH NH2 Compound 188 Compound 189 \ \
o 0 H2 0 0 0 N17rsr 0 0000 0 NH, HNyN OH OH OH OH
HN,,N OH OH OH OH ="- N -, N HO 6 -omersi H2N Me H,N Me0 () d o d .Nrc)..õ.r-N 0 'rNH
HO' OH ' N, NH
---c"

Compound 190 Compound 191 \ \
...N_-=\ [-_N
0 0 2 0 0 0 0 0 0 0 ci2 0 0 0 NH2 rsi''5_NH2 y-1.N , . , cy_c_j....N.,e,,,, 1 HNy.õ, OH OH OH OH , N: N
HN,,,N OH OH OH OH 0 time, -H2N Me0 0. / H2N Me \.....0___7....r.
y.NH
bH 1 Compound 192 Compound 193 \
1 HN ,,,N OH OH OH N
0. / H2N Me0 H2N Me0 d o 6 o o Ni=r\iv ,0 LX Nr'f yNH
HO -.6H NyNH
HO' .bil 0 Compound 194 Compound 195 \

+N=\
0 0 i=N NH2 0 0N,, -11 110 11 N , 'y HO OH OH OH , N, N
H2N Me0 oõp/,,_ H2N Me0 o, 0 f=_N

\........,Ne y-NH
N:yNH
HO\ ,OPH
HO' bH 0 Compound 196 Compound 197 \
P- -P-o HN ,--N O OH OH
HN ,N OH OH OH a, --me N N NI" HO - 0 OMe 0õ,z,/,_ H2N Me0 ( H2N Me0 6 o 0 \...,õ.0 r\r Li--N
rNH
HO' HO' " 0 bH y Date Recue/Date Received 2023-07-07 Compound 198 Compound 199 \ \
-,N=\

0 o o r=isi (D N 0 ''' HN ___. N 6 6H OH ' I
,õT Ho OMe HNN 6 OH 6H
, \- '"-r HO - d bMe ----'" 0 H2N Me0 ( H2N Mac) HN
Ny),,, ,r0 . . r NH
HO' - N , NH
u HO" '-õ 0 bH --r Compound 200 Compound 201 \ \
+N=\
0 0 0 i=N
7r\i''.5C) 0-P-O-P-O-P
(3 -0 N õ NH2 ., N,, 0 õ.2 0 0 P 0 P 0'.."--0-.*
HN ,...N 6 OH O
õN H I
-"- N HO , N HN, õ OH OH OH I
r --,-- HO - bMe H2N Me0 /CD H2N Me0 0, 0 .--0Et N"--"-- N
d 0 HN /=N

NO
HO' ,ir-NH
Ho' ' N õ NH
bH I
HO' ' 0 bH NH2 Compound 202 Compound 203 \
\ -,N=\
0 0 0 0 /=N

N.,,(\--õõf NH2 oYels4),. 'WS ' 'CI-P-0-P-0-P-0 'r4 NNH2 (DYYN'.5 '."0-P-0-1LO-P-0 HN ,õN OH OH OH ' 1 -. .- N, N HN ,...N ___ OH OH OH ' ' N , N
'Nr- HO d On-Pr '--' sr¨ HO d bEt "'-' O. /
O. / H2N Me0 H2N Me0 /=N?N

\ll¨NH
Ho' ' N , NH
HO' ' bH0 bH y Compound 204 Compound 205 \
\ +1\1=\ /=N
-,N=\ i=N 0 0 0 NH

0 0 0 0 '''',9 P 0 P 0 P
, II II II' I
o----Y .5 0-p-O-p-O-p-OY'''r NH2 HN .N OH OH OH : , N , N
HN __N OH OH OH -= __ -- N , N '7--- HO 0 01-Pr -r- HO d On- Pr -' 0. /
O. / H2N Me0 -P,-H2N Me0 , 0 cNo o,...rr-0 NH
F10'. ' N-, NH
HO' -.., u 0 bH y H

Compound 206 Compound 207 \
\ + N=\
+N=\
0 0 0 0 /=N
0 N,, 0 õ
0 NN?õ,, ,,c,NH2 'y-e\cr 5 - ""-o_Vo_Vo_Vo,"--c (:),N5 ''"0-P-O-P-0-P-0 HN ,N OH OH OH I
' ' N, N HN õ... N OH OH 6H
--r-- HO
--,-- HO d bi-Pr --.' o-. /
ch / H2N Me0 H2N Me0 Ni=Ne\N 0 ,ir-NH
N, NH
HO' --o1-1 0 bH y Compound 208 Compound 209 Date Recue/Date Received 2023-07-07 \
0 0 0 0 H2 ,y)y,,50 ,., NH
rr\l'.5o ''"0-P-O-P-0-P

-ONN
µ0J:PLOJP-0-1-0'..s-Cr' "N?''--ri 2 o HN --N OH OH OH -. ',õ Nõ,, N HN --N OH OH O
, v H -- -- N N
si-- HO u n-Bu - '7--- HO O. ome '--H2N Me 'P,- H2N Me 0 0/P'b 0 /=N

,ir-NH
0 H HO' OH - NyNHHO'--61-1 Compound 210 Compound 211 -FN=\

0 0 0 /=N
C)Nõ,5, 0NNH2 0,,yõ-cr, 0 N ON, 0 '''µO-P-O-P-O-P-0 NH2 HN __ N OH OH OH : __ == N, N HN --N OH OH OH
I
z -- N, N
)--- HO d bMe --'' -,¨ H.
H2N Me0 H2N Me 6 o 0,p!_ bme ----d o /--N
NN?õ,f0 HO' --HO' ' N , NH

u1-1 y Compound 212 Compound 213 p -FN=\

Y.-YN ' So ='µI0-1'-0-1'-0-1Ln-'11 y i NH2 0N,,õ., 11 11 11 (7)POPOP0'..--Lr. N?.'irNH2 HN _N OH OH OH -- __ -- bme N, N HN ,-- N OH OH OH -- -- N -- N
Nr HO -1--- HO d bme ----'"
H2N Me0 0,p/C:1_ --' H2N Me0 0, , 6 o 6 0 /=N
Nir-NH
HO' ' H N -- NH
OH HO' 0 NH2 Compound 214 Compound 215 P \
+1\1II II II
=\
0 0 0 /=N
04-04-04-0...._C).,NNNH2 -F N=\
oy_yN,,, 0 ,.õ04-04-04_0,.....0,0 '7--- HO
HN --N OH OH OH Ni=N?õcrN NH2 -. .= N -,,, N ,NH Me 0.,..pOS_ .. oMe "---'' )--- HO d bme '--' i 6 o o. /
H2N Me 'P,- N), 6 o iz T
\....,coy.Nr OH N, NH
,ir-NH I

HO' 'OH 0 Compound 216 Compound 217 \
\
-FN=\

0 0 0 0 o o o ,..,......ØõNN,NH2 II II II
P-O-P-O-P-0 Z i ---0_ ii ii -0.."- )'..1\INri OH OH OH -- , N, N
HN __N OH OH OH -= __ "-, _ õ,õ N HN _N
'7--- HO d bme '--' Nr- HO 0 OMe1\1 ¨ 0. /
0, / NH Me0 rõ.NH Me0 'P,- 6 i 6 o \=õc0"..Ni=N_ 0 N-T
. . =)r-NH N, NH
HO'OH OH I

Compound 218 Compound 219 Date Recue/Date Received 2023-07-07 \
\ -,N=\
0 1=N

-, N=\
0 0 0 0 Ni HN =r\j, .N .õ,, II II II
H, (jee\Cr'N 0 '1 0-P H -O-P-O-P-0 H OH N?---T-N,5 ,c,,,11_01,11_01,11 0 õ
__ N O O -= =- , HN __ N OH OH OH -= == N , N Nr-- HO d omeN N
-----"
-r- HO d bme '-' /
H2N Me0 NH Me0 /=N
=====,C)...NN?,f0 ,ir-NH
..L---/ HO'. ' N
, NH
HO' --OH 0 oMe y Compound 220 Compound 225 \
\ +1\1=\
0 rykrN NH2 + N=\ /=N 0 0 0 0 (D..õ,s,Nõ.50 ..,,,o_iv_o_ito_iv_. 0 yõTrNH2 oYe-Cr"\ 1\1"' o P, o i= o A o"-0"
HNõ. _.....-- N OH OH OH -= , N , N HN ..- N
f-- HO OH OH OH -"- N , N
d bMe ----7 r HO d Ohne --- o- /
/ H2N Me0 H2N Me (:)1',- 0 , o 6 o NI=N
{
c_Cfy.Nr------\r HO' ' N õ NH
HO' " bme On-Pr I

Compound 226 Compound 227 \
+ N=\
0 0 0 /=N
NNir,\õi H2 Oyci, 0 0 0 0 0 ),NrN 50 ,.õ,,, o N N- =."`o 0 0 P, o^0-"YjrNH2 N ' o-A-o-Vo-V
0,y OH OH OH - .- N
, N
HN ,N OH OH OH -= ==
HO d bme N , N HN ,N
N o r- HO 0'1-12 bMe ----7 Y . /
H2N Me0 H2N Me0 -P,- do / o o o cO__tNr c_i_..0 NO
Z
,ir-NH
HO" ' N , NH
bH y HO' - 0 On-Pr NH2 Compound 228 Compound 229 \ \
-,N=\ /N
0 0 0 /=N
o N , NH2 ON
N ''' 0 '."OPOPOPO'-s-t/..

(DN"5 '0-13"-0-01'-0-1:)"-0 I OH OH OH ' I
HN - N - - N , N
HN __ N OH OH OH = =- N , N 'T-- HO d "bme --,--- HO eH2 bMe ----"" 0, /
/ H2N Me0 H2N Me0 C)1:',- H26 6 o /=N
o N o Ho' ' N , NH
bH I
HO'. " 0 bH NH2 Compound 230 Compound 231 \
\ -F N=\

NH
oI-F =\N, 0 .. 0 0 o o i=" NH
'''YNI''' 0 O P 0 P 0 P 0...-.0-..Nr.)-õ1, 2 ,5 N11 II II I

H O OH O
N OH OH OH -= =- N , N 'r- HO - bme --'N
r HO 0, P blVie H2N Me0 ( H2N Me 0 H20/ /=N
\=õc0i...NNO
,ir-NH
HO'.--._ N , NH
HO'--,_ uld0 OH y Compound 232 Compound 233 Date Recue/Date Received 2023-07-07 \ \
-,1\1=\

9 9 9 ......_Cr 0 Y-S7N''' O I' CH2 iI: 0 iI: (D",?---r O-P-O-P-O-P-O I
I OH OH OH
HN ,... N
HN __ N O OH OH N NH2 -. == N , N Y HO
yHO - bme ------ 0. /
H2N Me0 ( H2N
OMe 6 o 0 /=N
Nir-NH
H HO' '_ N , NH
O' ' 0 OH ---r bH NH2 Compound 234 Compound 235 \
\ -F N=\
/=N1 + N=\ /=N 0 0 H 0 0 0 tl-c12_1(Lo_V,_0 0 r\i'.5 "" 0-A-04-C2-P-0 HNõ - N OH OH OH N y,õ1,7 i NH2 , -- N , N HN ,... N
--r- HO OH OH OH I
N , N
6 bme ----7 T HO 6 "OMe ""-"e 0õ,,,,_ H2N

OMe OMe O
roõ..N \,,,c5...Ni-N-N , NH
o HO' -N õ NH
-til-1 bH i Compound 236 Compound 237 \
\ *N¨\ /=N
Cl2 9 9 0 0 H 0 i:
Ny,õõc,NH2 0N50 .., N NH2 µ0-11LO-P-C2-P-0'-..---0-.' 0 P C I, 0 I, 0'...----0-' V
I
HN, _ N OH OH OH I
: =- N , N HN , N OH OH OH -= , N , N
y HO b. bme --' y Ho 6 bme ----OMe OMe 6 0 0 \11..N

,ir-NH
HO'' ' N , NH
.-1----/
HO' bH 0 OH i Compound 238 Compound 239 \
/=N 0 0 0 0 0 N Nr),,N H2 N,50 õõ.0_ A C12 _C -L 0 -1L0 0 N,,. ,.,,,, II II C12 II

NN "2 Y-ekNr HN ,... N OH OH OH N OH H H
I HN ...
Y HO O O
O -bme,N
y HO di OMe 0 OMe 0õp/ _ H2N
H2N , 0 6 0 OMe 0 NO
NH) ,ir-NH
HO' ' N , NH
HO' - 0 OH y 'OH

Compound 240 Compound 241 \ \
S 0 0 0 /=N\
0 0 ni 0 0 (DI\I '5 " 0 -ILO-A-C-2-1LO o N NI-12 5 VO-VO-A-0 ri\iNerINH2 I I I I HN ... N O O O ' ' N
N
, HN ,... N OH OH OH : ' N , N y HO H H H 6 bme Y HO O bMe --"- 0, /

H2N ,P_ "P.,-/ 0 OMe 6 OMe 0 yNH
y, HO' -OH HO' 0 -OH N
NH

Compound 242 Compound 243 Date Recue/Date Received 2023-07-07 \
\
+N=\ /=N +1\1=\
m 0 0 S 0 Orr\i", :Lo_ D D
Lo_L00NNH2 y-y".5 '"'0q_0_1_0+0"s-C.../- N NH, 1=1\
zNN'Tr HN ,N OH OH OH 1 N
-. .- , N HN ,...
HO
HO OH OH OH : -- N, N
d bme ----' Nr-- bmeN ----"
od . / H2N , H2N -P,- OMe 0 0 OMe 6 0 /=N

\,......CyNe HO' ' N , NH
H0. -oH o OH i Compound 244 Compound 245 \
\
+1\1=\
0 0 S 0 /=N

'5 P-O-P-0-P-0 N --N OH OH O
H H i ' ' N , N HN --N OH OH OH NN
'7--- HO d OMe 'sr HO = d bMe ------ 0, /

/ 0 OMe OMe 0 cID_y..Nr 0 /71\j N

yNN

NyNH
HO" --oH 0 Compound 246 Compound 247 \
\ -,1\1=\ 1=N
-FN=\
0 0 S 0 /=N\ NH y---y,,.5 _9_H_9_ :R_ 0 NN?7,,irNH2 N, OPNPOPO
0,y_iy 5 õ,,, II II II
''. 0-p-O-P-O-P-ONNe'ir 2 HN ,N OH OH OH
-= -- N, N
HN __N OH OH OH -= -- N , N si-- HO d oMe --------r- HO d bme --' o. /

H2N OMe 0 OMe 6 0 \,,,,,cto Ni-Nell 0 HO". ' N , NH
HO' " OH0 OH y Compound 248 Compound 249 \
\

-FN 1=N
=\
O: 0 0 , 0 0 0 H 0 0 0 H2 ,,,,, IN, ,.., II
II n ii .,......\,,o.7...Ny,H,,NH2

5 ='µµO-P-N-P-O-P-0 "Nri" 5 (:)-- -','-'1-- i HN __N OH OH OH _,,' --, NN HN __N
)--- HO OH OH OH : -- N , N
d OMe ----"
Nr- HO U OMe - O. /
-H2N C('P,- 0/
OMe OMe 0 \ir-NH
HO' - N , NH
OH
HO" - 0 OH i Compound 250 Compound 251 \

N "
oN50 .õ,,o_ii ii H ii OP01010' 13).'N .NirNH2 N?-y HNs, _.....--N OH OH OH , -- N
d , N , ,N OH OH OH OH , r HO
r HO d "OMe ----"" O. /
0. P H2N
H2N -P,- OMe 0 , 0 OMe 6 0 -N
cOyNr-------\r )r-NH
( HO' "bH
N.- NH
HO' -oH 0 Compound 252 Compound 253 Date Recue/Date Received 2023-07-07 \ \

+N=\
---Y''. 0 J, .II .II . 11 . 0 ,,(NH2 ,r,N,,. 0 ..,, 0 0 H2 0 0 I
HN, ___N OH OH OH OH I
-- , N, N HN, _...-N OH OH OH OH ."- N, N
T HO ci 'OMe '----' r H05-3 d bMe '-' 0,p,_ OMe 6 o OMe =N
c,"...D Nr-Ci rNH
HO' - OH N, NH
HO' " 0 ohl NH2 Compound 254 Compound 255 \
\ +N=\ /=N
0 " 0 -- NI
13y,,,N,,. 0 , 9 9 ci2 9 9 0 N
--''Y''' 0 I:j C H2 : ' 0 1j' 0 0 Ny..,NH2 N
, ____-N O O O O I N
-r- OH OH OH OH ' -N.-, N
HN H H H H , HO b' 'OMe -- .
r HO d bMe ---7 0, /
0, / H2N 1.õ-H2N OMe 6 o OMe 6 o 0 F¨N1 N

=NH
HO' - N, NH
'OH

Compound 256 Compound 257 \
\ +N=\

+N=\ =N Oy--cr,N,,,50 NH
0 "µµo o CC12 :1' 0 0 14- 2 HN õ.NN OH OH OH
0, / = == N, N
HN __N (SH OH OH OH -"- N, N Nr HO
NH OMe ---7 y HO d bme "'-' H2N 0,p/, _ OMe O OMe 0 0 /=N
\coy.,rro NH
HO' N, NH
'OH bH i Compound 258 Compound 259 \
\ +N=\
+N=\ /=N 0 0 oys,N,,s0 10 0 10 0 10 0,......0_...yrINH

OYI\l'.5 '''µO-Ig-O-P-0-1g-0-0-' -= -- N, N
OH OH OH ' I
= -- N OH OH OH
, N HN ,...N
)--- HO
r HO NH 'OMe ---"- O. /
0õ,,,,_ H2N -P,-OMe OMe 6 0 0 _N
\\,cy..0 Ni¨c) cOyd\rej NH
HO' ' N , NH
HO' "
OH o OH i Compound 260 Compound 261 \
\ +N=\ =N
+N=\ /=N i 0 0 0 0 0 0 NH 0y,,,50 YYN'.5 "0-11='-0-1L0-11=LOcC5-2.'N 0-P-O-P-O-P-ONNH2 O OH OH -. ..
N, N
HNõ N OH OH OH -- -- NJ , N HN ,... N
d bMe )--- HO ----7 r HO d oMe ' H2N ( H2N -P,- OMe OMe 0 c__Oi_a.Nr\r N0 ,tr-NH
HO ' N, NH
HO' -OH 0 OH y Compound 262 Compound 263 Date Recue/Date Received 2023-07-07 \ \
+N=\
0 0 0 /=N +N=\
K. 0 0 0 0 0 1=N
NH
. 0 ,õ,õ II II II 0, _N NH2 Oy-y.,.õ.., u u u ........., =.-..,.y.,\ 2 Or\I 1 0-P-O-P-O-P-0 7-- ,?--y OPOPOPO" --\_ Zi HN ,....N 6 6H 6H _"- HNN
Ho O OH OH
- -", N, N
OMe ---7 )--- HO - d OMe ----""
H2N ( H2N
OMe HN
OMe 0 /=N

\..õ0.,N0 NIT-NH H0 ' b N õ NH
---f-HO' ' 0 H
bH NH2 Compound 264 Compound 265 \
\ -,N=\
+N=\
1=N
0 0 0 0 \
NH2 ON.,.5 0 , ,õ II II II
N 0-P-O-P-O-P-0 )...."Nr-crNH2 O'-',r\i''.50 ="'o-Vo-Vo-VoNN?-ii HN --N O OH OH -", N, N HN --N HO OH OH OH -= -- N, N
Nr- HO - 0 H2N \'' bme ---' `f--(:),p,!_ bEt OMe HN /=N

\.*I5....Ni N, NH
HO' ' 0 OH I
bH NH2 Compound 266 Compound 267 \
\
+N=\
0 0 0 /=N
0 0 0 0 N z orr\j '''5 '."0-P-0-1g-O-P-0 NH
P, o o 11, o I
HN ,N OH OH O HN N H I
-= -- N , N ..--Nr- HO OH OH OH -- , NI, N
dOn-Pr ----' Nr- HO
H2N 0,,,t1._ bEt --'''' OMe 0 /=NN

,ir-NH
HO' ' N, NH
HO' " 0 bH N, bH NH, Compound 268 Compound 269 \
\ +N=\
1=N

+N=\
0 0 0 /=N 0 ,õ...õ II II II
Y--Y'5 0-P-O-P-O-P-0 NIN?")(NH, NH2 oY.Y"So ''ThD-F,'-0--0--0'-...--co)-'"Ne\---1( II II
HN ,....N OH OH OH -- -- N , N
HN ,....N OH OH OH -= -- N, N -r- HO
'Nr- HO d On-Pr --' 0. / H2N
H2N -P,- 0,p!_ 0, Pr OMe 0 OMe 0 _N
NO
rNH
A----/ bH HO' ' N , NH
HO' " 0 OH
y Compound 270 Compound 271 \
\ -,N=\
1=N
0 0 0 +N=\ /=N O), y.N(N,, 0 ,50 ,.õ,, II II II
,.......o....y,õ õ1,,NF12 0y,õNyN50 to1Lo_ito NN H2 N O-P-O-P-O-P-O I
HN ...--N OH OH OH -.' N , N
OH OH OH , -- Pr HO d On-Bu ----"..
r HO d b i- 0 õ, _ 0õ, _ H2N

OMe 6 0 OMe 0 ,ir-NH
.. . 1-10µ " N, NH
o HO' --,_ld 0 'OH y Compound 272 Compound 273 Date Recue/Date Received 2023-07-07 \
-,N=\ /=N

HN 2 0.y.- Nõ.50 ., 0 0 0 N
(DY''YN''5C) O-P-0-1ILO-P-00r "?'-ri "'o -Vo -A -o-A -o^0-4 ,?-)-(NH2 HN --N OH OH OH z -- N , N HN --N OH OH OH
HO d bn-Bu ---"" ' b. 7--- HO
/ 0, /
H2N (:)P,- H2N
OMe 6 c) OMe 6 _NI
-- \*.T3...NI¨Nr,r\-Nir-NH
A----( HO' u --_,H 0 H0 -- OH NyNH

Compound 274 Compound 275 -FN=\ 1 0 0 0 =N +1\1=\
0 0 0 0 /=N
Ny,\i,NH2 Orr\l',50 Vo-A-o-Vo"0"
CI N , NH2 ON,,5 II II II
N ' --Lr Z i HN --N OH OH OH I
-"- N -- N HN --N OH OH OH , -- N, N
HO 6 bMe "---"" ''''1- HO
0, / 0õp_ brVie H2N 'P,-OMe 6 H2N

0 OMe 0/
0 /=N
NN?õ,f0 HO"
HO' ' N, NH
---, 0 OH
uH i Compound 276 Compound 277 P
-FN=\ /=N -F1\1=\ 0 /=N

'O-P-O-P-O-P-Oor NN?(INH2 o NH2 N'So ."µo-Vo-A-o-A-o'..sscp'"Nr HN --N OH OH OH : == N, N HN õ-N OH OH OH --N, N
HO 0. 0Me ---"- ''''r- HO d bMe ----"-0, / 0, /
H2N 'P,- H2N
OMe 6 0 OMe 0 0 /=N
y0 H HO' ' N, NHHO'' OH OH i Compound 278 Compound 279 P \
-0\1=\

ol\i'''5 ''"0-P-O-P- /=N
0-pII-0,._\õ.0,r.NNH2 -F1\1=\ i=N
HN --N OH OH OH -- -- N, N
NH V_01:1V_0 2 'Nr-- HO d bMe HN --N OH OH OH NH I
, : -- N , N 0, /
)--- HO 6 OMe '-- i OMe 0 OMe OH N, NH
,ir-NH i HO' u .---H 0 Compound 280 Compound 281 \
\ +1\1=\ /=N
ONõ, 0 ,.õ(3_17,õ;)õõ_(3,...scr0 NH2 ONõ.50 ..õ0-0v0-0v0-0A-c(.......n....Nri NH2 HN __N OH OH OH -. '; N,,N HN õ..N
'7--- HO OH OH OH N, N

6 oMe ----'' '7--- HO 0 OMe ¨ 02p/ _ / NH
NH (:)P,- ci OMe 1 OMe 0 rN, , u_ Nr,ro Ho' ' N , NH
H0- "-OH 0 OH I

Compound 282 Compound 283 Date Recue/Date Received 2023-07-07 \
\ -,N=\ /=N

-,N=\
0 0 0 /=N 0 0 ,, II II II
N z NH2 N. N''' 0-P-O-P-O-P-0 7 i CIYYN'.50 O-P-O-P-O-P-0 OH OH OH
HN __ N OH OH OH I
-= -- N , N HN --N
'7--- HO d OMe )--- HO d bme -----' 0, /
H2N - P,-',TAN OMe 0 OMe d0 /
NH
HO'µ ' N , NH
OH
.-L--/
HO' = 0 OMe i Compound 284 Compound 289 \
\ -,N=\

+1\1=\
0 0 0 0 0 0 .õµ,_ II II II
N0 04_04_04_0,õ\,, õ? 1=NNH2 17_0 .,---yN, HN --N OH OH OH I
: __ ' , N HN --N
si-- HOs OH OH OH -= , N
, N
HO Ci OMe ----7 0, /
0, / H2N
H2N OMe 0 OMe O o /=N

,ir-NH
Hd --_ N , NH
HO' bme0 On-Pr i Compound 290 Compound 291 \

0 0 0 /=N
, 0 õ,,, II II II
N'5 0-P-O-P-O-P-0 FY-Tr .."-04-04-04II
-0---c )-iNH2 y OH OH OH - =-___ N , N
HN __N OH OH O H2N
H -= , N , N HN N
)--- HO C'H 2 OMe --,--- HO 0 oMe ----7 0, /
H2N 'P,- OMe 0 OMe O NH 0 /=N
r cOy.Nr\0.
.--_ N NH
, HO' --;. 0 HHO'OH
i un-Pr NH, Compound 292 Compound 293 \
\ + N=\
, 0 N 0 0 0 0 0 NI=N NH, -F 1\1=\ /= II II II
,5 ,.õ 9 9 9 ON 0 0-P -0-P -0-P-0 ) 0 Ny.\-õ,.1,õNH2 N' OPOPOPOr ''i.-7-\'-ir N --- y I HN ,...N OH OH OH : -= N,,, N
HN _N OH OH OH - __ , N , N )--- Ho si-- HO C-112 Ome -----"' 0, / H2N
HO / OMe H2d OMe 0 O NO
o coi...N-F-0 ,ir-NH
HO' OH N ---- NH
i HO' u --.,H 0 NH, Compound 294 Compound 295 \
\ +1\1=\ /=N
-F N=\ 1=N
N NH
0N,50 01)-0 II --OILlry7..N.,,,NH2 ().--/ -,.. 0 ¨0 ,v 0 iv 0 ,v 0-----\-0-7-- ,re\---3,- 2 NN
HN _N OH OH OH I
-= __ =- N , N HN
)--- HO O OH OH
- & bMe ---

7 si-- HO d ( 0 oMe ---7 H2N, /
HO 'P,- OMe 0 OMe H2C/ \=,., µ
_O NI=N
N?,f0 Nir-NH
HO'' N , NH
HO' u =õ 0 H OH ---1--Compound 296 Compound 297 Date Recue/Date Received 2023-07-07 \ \
-FN=\
0 0 0 /=N -FN=\

0 i=1\1 NH2 0 N Nirv,V.i NH2 ON, .
Oyi\i'50 '''µO-P-O-P-0-1g-0 Yy HNõ,,N O OH OH i -- -- N, N HNN OH OH OH
d. ---omeN N
---.7"--r Ho T HO - . -0Me ---7 0,,p,,,_ ( H2N HN
OMe 0 H
cOy..NTr?\je, ,ir-NH
HO' ' -OH N.,I NH
HO". u ,..., 0 Compound 298 Compound 299 \
\ +N=\
-FNI=\ /=N 0 0 0 Oyõ.y,,.5 ..,µ,04-04-0-vo,.....,Cr N NI-12 II

0 II' 0 I' NH2 i HN,,N OH OH OH : , HN ,....N OH OH OH -- -- N.õ N T HO
y HO d oMe ----"
O. / H2N 0õFt OM '--0 d i\e pl Z
HO" ' N .õ NH
-OH i HO' OH 0 Compound 300 Compound 301 \
0 0 0 -FNI=\
0 0 0 /=N 0 0 N,,õ.,,,,_ II II II a Ni=N NH2 O-O \-iN1-12 'Y---µ").V 0-P-O-P-O-P-0 Nr-V--117 HN ...--N OH OH OH : I
-- , N HNN HO õ _...- OH OH OH ' ' -0Me N, N
r d "--7 '1"-- HO d bMeN "--" O. /
0. / H2N HN

o d z HO' ' N NH
HO' -OH0 OH i Compound 302 Compound 303 \
\ *N =\
-FN=\ /=N 0 0 0 0 rN

0N,.50 .,õ 9 9 9 2 I' 0 I' 0 F' 0 NH , ---""--0-= ,?"---r OH OH OH -- , N, N HN õ...N
Nie-- HO OH OH OH -= -= N
r d HO bme ----7 o. / d H2N HN
bme --' ,ir-NH
( \.....õ( \...0 I=N
HO' O, H NyNH
.
HO' u--õ 0H NH2 Compound 304 Compound 305 \ \

0 0 0 i=N
o N,NH2 50 ,,,,õ II II II õ.......,n...NNH2 0 ,N,.Ø."-olgolgoAo----0--HN ,....N OH OH OH I
: -- N., N HN .N OH OH OH .. : , .. N
)--- HO d bme '--' )--- HO d bme '-' o, /
o. / _ H2N HN -P,-/=N1 d ,C) 1------r NyNH
HO N NH
HO' ' 0 OH
' ' .õ
OH ---r Compound 306 Compound 307 Date Recue/Date Received 2023-07-07 \
\ +1\1=\ /=N
-F 1\1=\ /=N 0 0 0 N Ncr,v,i NH2 5 ,,,, ii ii ii N

oyyN'10 '''04-04-04-0 OH OH OH ' I
: , N .õ N HN s, ...-- N
y HO d bme '--HO 0.,p/õ._ 0,p/d_ bme '-' o co_y. rNr CS C o\ . _ 0 NI=N
-T____)- -?--fo =77.-NH
NH
HO'."- O N ---H iHO' u "-- H0 NH2 Compound 308 Compound 309 \
\ -,N=\
0 0 0 /=N 0 0 0 2 II II II 0 Ni=N,.. _NH2 01\i''.5 .'" t7)-ii -0-1L0-iL0o)-"N'ri NH Nry HN _..N OH OH OH -= __ =- N ., N HN ,...N
'''1- HO OH OH OH : -- N .õ N
Nr- HO d OM e ------' oõ,,,/ _ H2N HN
H2N HN .0 O._ bme / o o 41, o o r\' \*...TCYNyNH N0 HO' .--_ N .õ
NH
OH HO' --_, 0 H OH i Compound 310 Compound 311 \
\ -FN=\
-F N=\ /=N 0 0 0 0 0 0 0 H2 N NI, ,.,Thj 0 0 0 0 r7N

o'Nj 5 V 0-Fi II II
N (:) 5 õ ,N?jr HN ,...N OH OH OH : =/, HN ,....N OH OH OH '''r-- HO d OMe "--"
-T--- HO d OM e ----7 0,..p/ _ H2N HN , H2N HN ,0 .'s--- 6 o o / o -ss - 0-6 ,=1\I
N j 0" \ 0 r \r"----\=.,,c5...y,,e \''....Q. -"Nir-NH
HO.' ."- NyNH
HO' " 0 OH
OH

Compound 312 Compound 313 \
\ +1\1=\
-F I\1=\ /=N 0 0 0 0 i=i\I NH2 (=1,y ,.50 H H H .,õ =),õ---õcr,N,..50v II II II
0'....--0-.'NN-fr ,...N OH OH OH
0-: ,bme HO N N
O O O : =- NI ., N HO '7"-----7"---Nr d bMe -----7 0õ,,,,_ H2N -N
H2N HN ,0 (:) do / o 0 ,=N

. . , H0,, , OH N_ NH
u HO' _____________________ õH 0 Compound 314 Compound 315 \

NH2 N ' '''''.0-1'-0-P-0-1'-0N y i NH2 0 -A-o--o-i ii Lo"-0-- y i OH OH OH -- --NI ., N
OH OH OH '. ' N , N HN , N
'7"-- HO Ci bMe ---HO

N 0I=
r'Nf Z
HO' OH HO' O
.--_H N ., NH
" 0 i Compound 316 Compound 317 Date Recue/Date Received 2023-07-07 \
\ -,N=\
/=N 0 0 0 ,HHH

ON,,.50 ..õ04_04_04_00..N7 NH2 N N''' I
HN ___N OH OH OH 1 : __ ' N , N HN N OH OH OH -= " N -- N
-,--- HO d bme Nr- HO d bme o,p, _ 0õ,,,, _ H2N

N

0 '0 0\ ro Ni=N
1y, NH
r NH
H0 u ":õH NyNH
HO' --,_,H 0 u Compound 318 Compound 319 \
\ *1\1=\ /=N
-FN=\ 1=N 0 0 0 0 0 0\1\1,050 LHPiLo NNNH2 N N''' I
I I I I HN õN OH OH OH -= " N, N
HN ,N OH OH OH -= " N O
, N Ni- HO 6 H2N bme ----7 Nr HO 6 OMe ---7 0õ1:,/ _ H2N

NH
0 3-. rNc) HN
0 1:C)yN/7?fN 0 Z
rNH
H' --_,H NyNH
HO' "
OH0 u Compound 320 Compound 321 \
\ *N=\ /=N
-FN=\ 1=N 0 0 0 0 0 (:),.50 ..õ04_04_04_0,....__cONNH2 o A o o , , , HN __N OH OH OH I
-- __ " N, N HN ___N
)--- HO OH OH OH , " N, N
d -ome ---,--- HO d bme '--' oõ,,,,_ H2N HN

o o i_oi....NTI?\10 HN \

Hd ' N , NH
HO' - 0 OH OH y Compound 322 Compound 323 \
\
(:)+NI=L, 0 Th :):_o:_c):_c),.......O...N/71\
-FN=, /=N

5,0,cõ,,0_,LNH2 Nõ II II
HN __N OH OH OH z " N, N HN ,N OH OH OH I
-= " N, N
)--- HO d bme --' si-- HO d bme '--' o,pz_ H2N HN

0 H2N \*,c0"..N?,.,.e 0 \..:_i .N-r<Nr \ 7 NH
, y HO.
OH N NH
HO' OH 0 Compound 324 Compound 325 \
-FN=\ /=N

Oyõ,40syN,05,0 .0 NH
2 Y--YN''' "µTh) 13 CH2 IV 0 IV 0 ' 0 - A -o -V o - A
HN __N OH OH OH I
: " N, N HN ,N HO OH OH OH -. .. Ny õrNzt .N NH2 )-----,¨ Me ---7 0,6 b p,_ AcHN 0,1:e_ O
HO Me '-\ ...........0 N (3 I=N

C' y=NrN
Nir-NH H
d ' N , NH
,-u HO' _, 0 H OH y Compound 326 Compound 327 Date Recue/Date Received 2023-07-07 \
+1\1=\ /=N 0 0 0 H 0 0 , 0 0 0õ......O,Ni=yr,\õõirN NH2 OYYN''' 0 '''µO-P-.C2-A-O-A-0 c)Nj''. O P 0 P C2 I HN _.-N OH OH OH
cl' --bmeN N
HN,N OH OH OH , , N, N )--- HO --.."---T HO d bme -----"
ci,Fz H2N AcHN
H2N AcHN / 0 6 o o o coi_..Nr--\r \*===)-- .....N,,?...,t ' , HO' bH 0 HO N NH bH y Compound 328 Compound 329 \
\ *N =\ /=N
+1\1=\ 1=N 0 12 0 0 Nyhr,NH, (:),---yNõ,50 (L0_(Lc _ri,_0,.......coi.NNH2 o'yeSzN''' HN õ..N OH OH OH -= , N, N
HN õ..N OH OH OH -= == N, N )--- HO
)--- HO d -Me ---7 0i_ H2N AcHN 0_ ome H2N AcHN / 0 0 NI=N
coi__Nr----Nro Nyo u H Ny..., NH
. HO' O' --._ 0 --OH
H NH, Compound 330 Compound 331 \
0 0 0, ci2 0 Oyõ,yN,(0 ,.õ..., II Cl2 ? IFII 0,7..."NH2 (:)----Y, N, ,õµ, ii OPOPC PC(..strN
HNõ õ..-N OH OH OH -"- N, N
HN --N ) OH OH OH -- -- N, N r HO 0, P Me '7--- HO d bme ----7 oõF,_ H2N AcHN
H2N AcHN
6 0 d0 NrN
\co_y_N-r-Nro --u¨ -?----o \11,-NH
HO' HO' ' N, NH
' - - bH 0 bH 1 Compound 332 Compound 333 \
\ + *N /=N
1\1=\ /=N 0 S 0 0 0 NH2 0 CI a N , NH2 ..,.... II II
II N
(DYS/1\1'50'"0-P-0-1LC2-1'-0 OPOPOPO Zi HN _N OH OH OH ' I
N, H HN ,N OH OH OH
J ,bmeN N
--..7---)--- HO
Nr HO d bme -----" o_ ch / H2N AcHN
H2N AcHN / 0 \'''D....NN?,,eD
,ir-NH
H HO' ' N, NH
0 --õ uH 0 bH

Compound 334 Compound 335 \
\ +1\1=\
-F1\1=\ 1=N 0 0 S 0 NH2 O'ye"1",r, (:),,,,,,/,,y N II II II 0).....No ig o i A0 g o N1 NH2 HNõ õ,- OH OH OH -- N, N
HN õ...N H H O
N , H -= , N, N r HO
d bme '---,--- HO d olVle ---/ O. /
. / _ H2N AcHN H2N AcHN QP, 0/
d0 ,ir-NH
, HO' u HO' ' N, NH
--.-_,H 0 bH i Compound 336 Compound 337 Date Recue/Date Received 2023-07-07 \
\ =N +1\1=\
0 0 S 0 rN
-, N=\ /, ,, II II II
o 0 S 0 NH2 N OPOPOPOr NH2 , (jr\l 1 'µµO-P-0 II -1-0-P-0'-'..--0-'. N?(I o N
' 5:C-1 HN õN OH OH OH : =- , N
HN õN OH OH OH -- -- N , N Nr HO d -MeN

NI-- HO d bme --' o, /
O _ / H2N AcHN -P,-H2N AcHN 0 , 0 i=N
\.....2cOyNiye,tp r-NH
N , NH
HO' o --..H 0 OH i Compound 338 Compound 339 \
\ + N=\
-FN=\
0 0 S 0 rN ii NH2 (ji\i'.5 0-1g-kl-P-0-1g-Or NN?(i NH2 Nõ,50 ..µ ,0_1i;LL
o OH OM OH
HN ,-N OH OH OH : ' N , N HN 2õN
Nr"-- HO d bme --'1--- HO O bMe ---7 0, /
0, / H2N AcHN
H2N AcHN

Ny,,,L.f.

,ir-NH
N , NH
bN
HO' " 0 -OH i Compound 340 Compound 341 \

0 N 0 ii ii H ii .,..õ......c,OrNyzõV2,T,NH2 0yN5 ,-,0_4_,PL0HPLcNr7 NH2 yee-cr"..'S '''O-P-O-P-N-P-0 I
HN 2õN OH OH OH I
HN õN
NI- HO OH OH OH -= , N, N
d oMe --""
Nr HO d bme '-=
o. / H2N AcHN 'F',-H2N AcHN
ci coy..Nli=N
c_Oy.rNr N?-'fC) r-NH
N , NH
HO' -6H 0 -OH N-Compound 342 Compound 343 \ \
-FN=\ 1=N -,-N-_=\

0 0 0 0 0 F=N
1:3 H 04-04-N4-0 HN ,-N OM OH OM I
N -- == , HN 7. N
bkie HO OH OH OH OH , -, N, N
N
O. 'sr HO d bme ----7 o. / H2N AcHN
H2N AcHN 6 0 i_0_ya.rN N 0 HO' - N, NH
OH I
HO' -OH 0 NH2 Compound 344 Compound 345 \
= 1\1=\ i=1\1 Ny.iNH2 oy-kyN,,, 0 UN NH2 c) ig c=4 c4 Olg 0 HN OPOPC PP ./H
III 1 i HN ,N OH OH OH OH
N , - N -, N
, OH OH OH OH , ,-,,-- HO d bme ,,--- HO d 'Me ----"" c 0, /
0. / H2N AcHN
H2N AcHN -P,- ci 00 ¨N
....c_t0 NT--,y0 i:Oy.Nr-Nr ,ir-NH
HO bH
N-.õ(NH

Compound 346 Compound 347 Date Recue/Date Received 2023-07-07 \
+N=\ R /=N 0 0 0 ci2 0 0 0 0 0 0 IP 0 l'' 02 i4 0 0 o-ILO4--c -Vo-Vo'-')." 7 1 ' I ,N OH OH OH OH / = N , N
HN __ N OH OH OH OH , , N , N r HO Ci bMe ---/' -,--- Ho ci bme '--' 0,,z _ 0_ / H2N AcHN
H2N AcHN Or coyd--=--'Nro Ny),.,ro r NH
HO' 'OHN, ,NH
-OH I

Compound 348 Compound 349 \
\ -,N=\ /=N
+N=\ 0 0 0 0 0 ci 2 0 0 i=N
NI, 0 NH2 (j,NI''.5 'µµO P 0 P 0 P 0 ..---0--. NY'ri NH2 (:), . 0 P 0 P C P 0 IP 0"....--CrN I HN õ..
N OH OH OH - =-__ N._ HN .N OH OH OH OH z , N , N '7--- HO NH UlMe ¨
-,--- HO Ci bMe ----".. 0õ=
_ / H2N AcHN p H2N AcHN
6 o c) o N 0 /=N
r \...Ø..y.),,f0 NH N
HO'' N , NH
Old OH y Compound 350 Compound 351 \
\ +N=\
+ N=\ /=N r\\IH

0-P-O-P-0-1P-0 N , NH2 (3y-INI7N, N'''5 o-PII _o_PII_O_PII _0-'''''--C).='`NN., HN õ... N OH OH OH I
. .--_, N , N HN, _ N OH OH OH
ci' --bm. N
N
----.7"-r HO
--,-- HO NHI uMe 0. / H2N AcHN P.
H2N AcHN P / 0 0 /=N
c_0j...N ---rNro NH
HO' ' N , NH
OH i OH

Compound 352 Compound 353 \
\ +N=\
+ N=\ 0 0 0 (:),N50 ,,0-0A-0-01,to_OlitooN Nr7 , 0 .õ ..õ II II II 0 Ni=N NH2 NH 'y'''''Cr,'N'5 ' HN ,..- N OH OH OH i ' ' N , N HN õ.. N
'7--- HO O OH OH -. -- N , N
b. bme '--' Nr- HO d bme -----' oõ,,,,_ H2N AcHN ( H2N AcHN
6 o o /N
\,.., , _cp r-Nr NH Li- N o HO' OH
HO'' N , NH
-t)1-1 y Compound 354 Compound 355 \ \
+ N=\ /=N
0 0 0 0 N NH2 o OPOPOPO
C),1\1"5 'µµo-Vo-A-o-A-0"0" ,?-y O OH OH : .- N , N
HN õõ N O OH OH -. .- N ., N HN õ.. N
=)---"cN,,, n..0, 0õ 0õ 0õ
-,--- HO - N N H 2 bm' e "----r-- HO - d bme ---' H2N AcHN ( H2N AcHN
HN
0 /=N

,ir-NH
HO' ' OH N0 NH

N , NH
HO' "-_. 0 H NH2 Compound 356 Compound 357 Date Recue/Date Received 2023-07-07 \
\ +N=\
+ N=\ /=N 0 0 0 0 /=N

(Dy.y,,50 ,.õ0_A-0-A-0-vo,.,.cOrN NrNH2 ').-----Y. 0 õµµ, I, I, I, N,..5 OPOPOPO )--NY--cr HN., N O OH OH i . __ . N --, N HN, _.-N OH OH OH ,-- =-õ_ N N
---v---r HO
r HO - \''. -bMe H2N AcHN /0 H2N AcHN 'Põ-HN /=N

=,,,r_2õ, N 0 HO bH N y NH
HO' -1._ 0 'OH NH2 Compound 358 Compound 359 \
+ N=\
0 0 NH /=N 0 0 0 0 N N,,, 0 .. 0 N , 2 "oAooA
(:) o --S,"'..5 o-A 0 -o-A-o-A-0 O N
HN N , _.- OH OH OH -. ' N d bn-Pr -, N , _,,--r HO OH OH OH , -- N''-' , N
HN N
r Ho 6 OE t --' 0. / H2N AcHN
H2N AcHN
o cOi....Nr 0 N

Nir-NH
HO' ' bH N -õ NH
i HO' bH NH2 Compound 360 Compound 361 \
\ ,-N=\ /=N
-,N=\
o o 0 /=N 0y,,N,.,e),.õ 9 (DYYN'S o-A-o-A-o-A-o N.,,,e\--i NH2 s's.
OPOPOPO' -7.-- N?ly HN -- N OH OH OH I
-- -- N N HN ..-- N
're HO OH OH OH , -- N -õ N
d 0,-Pr )---- HO d On-Pr ---"- 0, /
H2N AcHN
H2N AcHN 'P,- d d \..õ.o....0 N o =.õc_Oy.Nr-----Nr V
Ng-NH HO'N yNH
'OH, HO. --0H 0 Compound 362 Compound 363 \
\ ,-N=\

+ N=\ 1=N
OyyN,,,), ,., ci,LsyN50 ..,,,o_itoji_o_itoor NN?õ..rN H2 N
(:)-A-0-A-0-A-Or0Ni=N?-'-crN NH2 HN, _ N OH OH OH I
-- -- N N HN, _,,-- N
r HO OH OH OH -.
d On r HO d oi-Pr ''-r 0, / H2N AcHN -P,-H2N AcHN
NNO
,ir-NH
. HO' ' bH N NH
HO' ". 0 uH i Compound 364 Compound 365 \
+ N=\ /=N +N=\ /=N

-"0-1'-0-P-O-P-Oo N N?-y NH
y-Y"'.. -"-OA0A0A0----c)-- z I
HN N OH OH OH -- '- N ,õ N HN __ N OH OH OH -- =-N , N
HO 6 On Bu ---7 NI"- HO Ci oMe ---7 0, / 0, /
H2N AcHN - P,,- H2N AcHN ' P,-0 /=N
rNH r ,...N 0 ,ir--HO" ' N , NH
HO' u -_, 0 bH i H

Compound 366 Compound 367 Date Recue/Date Received 2023-07-07 -,N=\ 0 0 Oi 0 N
II 0,....Ø00 NH, yyNH2 0N ,.õ,0 (:)1\I 50 0 0 0 0 'ThD-P-O-P-O-P-0 r II
HN ...-- N OH OH OH __,.' ",,_, N -, N HN, õ.-- N
OH OH OH : =- N , N
si-- HO u uMe ----"" r HO d oMe ----7 H2N AcHN 'P,- H2N AcHN
\''0...Np r-NH
=
H HHO'' N NHHO'O
--H 0 OH --r Compound 368 Compound 369 P
-,N=\ +1\1=\ i=N
ON ,,,(0 ,.µ, 9 9 9 0 N/=NV NH2 0, / N. 0 ..õ 9 9 9 0 Ki 1. NH2 0-P-O-P-O-P-0-=r Nry '/"---"-r 5----rI
HN ...-- N ; OH OH OH : ' N -, N HNõ ___.- N
OH OH OH -- --Nr- HO d bMe ----'' r HO
o, /
H2N AcHN 'P,- H2N AcHN
0 i=i\I
=.õi__O_y..Nr----Nr N0 yNH
H HHO'OH ' N , NHHO'--, 0 OH i Compound 370 Compound 371 P

-F \
N=\
0 0 0 0 i=1\1 C)I\I '5 V 0 P 0 P 0 P 0....--0-"NrI NH2 0 0 0 0 H HN õ .N OH OH OH
(37r\I "5 ='" CD-P-O-P-O-P-ONN?iNI 2 'Nr-- HO me 0, P
HN ,N HO d bme OH OH OH -= -- N ..., N r..NH
AcHN
sr- -----' I d H2N AcHN

0 yV T

Hd ' N .....
NH
OH i Nir-NH

HO'' Compound 372 Compound 373 \
\ *N=-\

0 0 0 ,,, II II II 0 Ni=N NH2 ,1\i'S '." C)-P-O-P-O-P-0 o---(N'5 '."0-P-O-P-O-P-0"...--0-.' HN, õ...-- N OH OH OH I
-. ' HN, - N OH OH OH : =-N , N
r HO d 'OMe r HO d bMe ----"' 0, /
AcHN ',TAN AcHN
õ..NH
_O NI=N
\.,co_i_Nr--Nro -?----o yNH
HO' , N --- NH
OH i HO' .--OH NH2 Compound 374 Compound 375 \
\ +1\1=\ /=N
/=N 0 0 0 O
0 0 0 0 ..,,,, II II II
µ,...._....
o'...Y1\1''' IO (' r\ NH2 Y---ri HNõ _ N OH OH OH nneN
HN N , _....-- OH OH OH -= -- N d -,o N r HO Ny-_NH2 r HO O bm. "-- oõ1õ,_ o. / H2N AcHN
Nr NH AcHN

\hlyN0 yNH
.-L---/ H
HHO'"zi-sH 0HO'bm. "
--r j,.

¨NHN2H
Compound 376 Compound 381 Date Recue/Date Received 2023-07-07 \
\ +1\1=\ 0 Ni=N

+N=\

0 N1=N\ NH2 C)y--Cr. 'N'S '''"NO-IILO-P-0-1L0 _II_ _II_ _II_ 0 i'0 P 0 P Oc r r''Ir 6H 0H OH
HN --N -= , NI, N
HN --N OH OH OH -- =- NI, N Nr HO d bme ------' Nr HO d Ome ------" o. /
o. / H2N AcHN
H2N AcHN do ci /=N

r CC'i...NrNNH 2....
N, NH
HO' "

bme On-Pr i NH, Compound 382 Compound 383 \
\ -,N=\
+N=\
0 0 0 /=N

0 yyNõ,50 ..,04_04_04_0(5...NN?rNH2 '."----'Lr'. 'N''. .'"0-P-O-P-0-1g-ONI=ZNI
I
HN --N OH OH OH HN ,...N
-7-- HO OH OH OH = --,_ N N
CH2 come ---7----si-- HO
H2N AcHN 0, /
H2N AcHN (:) !:( .OMeN'`''- N
'P, 50 (0__t.NrNr \h.i2....Ne rNH
OH
H N, NH
O' ' HO' --On-Pr y Compound 384 Compound 385 \
\ +1\1=\ /=N
+N=\ 1=N 0 Oy--yN"s (:)+0+0+0,....._0 ___________________________________ TrN1-12 (j,Nr\i''')(o.µµ0-(:), -o-olgi -o-olgi -o'-s- )--.NN?-,NH2 HN --N OH OH OH -= -- N
N
HN --N OH OH OH -. ' N , N Nr HO d Ome ----------r- HO CH2 OMe "---' 0, / H2N AcHN
H2N AcHN

\*""=Cy...N0 Nir-NH
HO' ' N , NH
HO' ' OH0 OH y Compound 386 Compound 387 \
\ + NI=\ /=N
+N=\
0 0 0 /=N 0 0N,., ,.õo_rNyr 7 i NH2 y--.õ,cr,N,..5 .,,,,, II II II

-.i HN ..-- N O OH OH -- N, N
HN ,...N OH OH OH : =- NI, N Nr- HO - Ome --0, Nr HO d bMe "--7 H2N AcHN /
H2N AcHN(0 H26 '' N

N
NH HO
.' ' OH N, NH
- y HO' " 0 Compound 388 Compound 389 \
\ +N=\
0 0 0 O /=N
+N=\
0 0 0 /=N
Ol\i'''50 =."o-Vo-A-o-A-o^-0--N'T''''---.(/NH2 0 N y NH2 P-0-0.-o-A-o i HN __N O OH OH i -= , N, N HN _N
si-- HO OH OH OH
si-- HO - OMe "--7 H2N 0, /
"Põ-H2N AcHN
( 0 NH2 d o o c0"..N/=N

NI)-Y7o HO' OH N , NH
u HO' "-_.H 0 y Compound 390 Compound 391 Date Recue/Date Received 2023-07-07 \
\ -,1\1=\
/=-N
0 0 0 F=N 0 0 0 0.,y,yN=,50 ..,,,O-PII -0-PII _o_cr.,....ONNH2 1\11110 '1" P-0 HN ,N OH OH OH 1 HN __ N OH OH OH
ome N -%N
= ' N ., N __ --,--- HO
si-- HO 0., p ome ------ H2N
0 N.---H2N 'P,- 0 0 NH2 d H
r N N r NN.r0 Hd H
' H
u Hd "-._H 0 OH
Ny N

Compound 392 Compound 393 \
\ + N=\
0 0 0 o /=N
*N=\
0 0 0 r= N 0y),NyN3,0 ,.õ,,, II
YYN''50 '."0-P-O-P-O-P-0 N NH2 / 0-III -0--0-pli-ON NH2 si-- HO OH OH OH N , N
d bme =----' --,--- HO d -ome N N
H2N --, -P,-0 N.--- 0 NO

c0".Nr\r1---?...r H
Hd --__ N , NH
uH
Hd 1", 0 0H y Compound 394 Compound 395 \
\ -,1\1=\
0 0 0 /=N
-,1\1=\ 0 N.,50 .õ,, -11- -11-_ NINI NH2 11µµ 0 -1'-0 -A-0 -1L0'-'''..(_ j"...NNH2 OH OH OH

= ' N , N HN ,N
si-- HO (f -bme N -'N
--,--- HO
d bme H2N O. /
H2N N--..'"- 0 .^-, NO

'\f .r H
rNH
Hd .--__H N , NH
Hd u ."-_.HID 0 y Compound 396 Compound 397 \
\ -,1\1=\
/=-1\1 -,1\1=\ 0 0 0 0,y,crN.,5 ,õ,..., II II 0 3,0 ,.õ,,0:õ-0-1 z.õ-0-01,.õ-00 N/=-NrNNH2 N 0-P-O-P-O-P-ON Nr NH2 HN ,N OH OH OH 1 HN __ N
--,--- HO OH OH OH I
d ome N N
si-- HO
. /
d bme N N H2N o. /

.-----õ,---N'''' d o H

c0)_.. /N

rNH
HO'1 ' N , NH
Hd u .--,_H 0 OH y Compound 398 Compound 399 \
\ -,N=\
-,N=\ 0 /N 0 0 0 0 50 ,.0(:) jiLO_FLO II
--0 N yrf\IH2 Y-1 1 .1" (21 F' 0 F' 0 1I o_y=N

di 1--0Me N"--'1--= IN
OH OH OH -,--- HO
si-- HO
. /
d bme N N H2N
H2N 0 Nj''== 0 0 N'-' 0 H
F=N
H
\*....ri.,0 Ny).7,,,,r.

rNH Hd ' N , NH
OH y Hd ."-_ 0 uH NH2 Compound 400 Compound 401 Date Recue/Date Received 2023-07-07 \ \

/N+ N=\

ON.' N O =''µO i=oi=oi=o N NH2 HN __ N OH OH OH 1 - ' N , N HN ,...N OH OH OH 1 --r-- HO
d Me -,--- HO
, / bd me N N
H2N H2N QP, O N 0/ 0 N0õ.
d OH
H

cOi...r\r NH H
.,c__3__[=,\,0 r rNH
HO' u .--,_H 0 HO' u .--._H 0 Compound 402 Compound 403 \ \
+N=\
0 0 0 /=1\1 +N=\ /=N
0 ,õ,..õ ii ii ii N 0 0 0 0 0 ---'1\i''' 5 ol-o-17-o H l-o"O N O ''"OPOPOPO 0 HN ,N OH O OH
' .":_. N , NH HN ,...N OH OH OH 1 = ' N , N
'sr HO 0, u uMe y -,--- Ho d bme H2N -P, NH2 H2N
o N(:) d =-z OH 0 N.--,õ.

c c5a.. r=r\I (::),.. r=1\1 Ny7),õõr0 Ny0 HO'. u .--_,H NHO'OH , NH H ' N , NH
y y Compound 404 Compound 405 \
/=N

Y--YN''' ('l'' O'as."Nr/ 1 ON,,, .."'o-Vo-Vo-VONNrk"-irNH 2 HN __ N OH OH OH HN ,...N OH OH OH
y HO = ' N , N
O bme y HO
d --ome N N H2N ..--..õ o. /
H2N 'P,- 0 N 0 / 0 0 N d L--..
I o C y-.CNNH r \,,coy.ri\HO
,,r r HO' ' N, NH
HO'- OH y .0H NH2 Compound 406 Compound 407 \
F=N
*N=\ 0 0 0 0 0 0 0 /N 0 N,, 0 ,, õ, NH2 0 N,,,5 ,õ,õ _ii_ 7 1 NH2 Y--'s 1 '' 0('OPOPO"...--Q-4 N --/' HN ...-N OH OH OH = ' N , N HN _- N
-,--- HO OH OH OH
0õ4 --C)Nie N N
--r-- HO
d bme H2N
H2N -P,- 0 N -(j ----..., d 00 fTerNi\ 0 0--rNrj...N
rNH
HO" ' N , NH
HO'u H ."-_. 0 OH y Compound 408 Compound 409 \
\ *N=\ /=N

+N=\
0 0 0 0 r=N ii ii .. ii 0.y--crN..,50 ,,,,,, ii 1----YN''' HN ,N OH OH OH 1 HN --N OH OH
' ./ N , N y HO 0, p bme -,--- HO 0, d oMe "=-="" H2N "Põ-H2N 'P,- 0 N(:) O N(:) d I o CDy-.N \=õcOyN/=NI\ 0 Nr rNH
HO' ' N , NH
HO"u H ."-__ 0 OH y Compound 410 Compound 411 Date Recue/Date Received 2023-07-07 \
\ -F -, N=\ /=N
N=\ 0 0 0 0 0 0 0 0 /=1\1 H H H
'5 '''µO-P-0-A-0-P-ONrNH2 OPOPOPONN)NH, 1 h HN __ N OH OH OH 1 - ' HN ,... N OH OH OH
--,--- HO d bme o. / - .- N
y HO
d bme H2N 0 O a cOi...r\r ,N r__ Oy NO
N
N?.r NH
Hd ' N , NH
HO'H 0 bH
uH NH2 Compound 412 Compound 413 \
*N =\ 0õ.Ny 50rolLto_LON NH2 V--.0-0V0-0V0-0V0,-...-0.... Nr=NH2 1 HN -- N OH OH N , N
OH OH OH , N sr HO 0., p ome -----si-- HO
0, /
d ome H2N

H2N - P,-o 0 a 'Y. ' P,-0 a y HN
,N, 0 NrNr NO
,ir-NH ==1---/
HO' =-__ N , NH
Hd OH y 0- H a Compound 414 Compound 415 \
\ -,N=\
O 0 0 -, N=\ 0 0 N , 0 0 0 0 0 i\l/= ON
(:)-Vo-Vcr-Vo^-0."'"NN H2 II II II
0 17 0 17 0 17 Cr-4'..-0-.'Ny%KrNH2 I d --omeNN
HN __ N OH OH OH = N , N Nr HO
--r-- HO
d bme H2N -P,-,y0 0 a H2N -,r0 ' P,-O a c HN HN,.."-, .--= O.y..N/=1\1 r- \r---- 0 NO
)T- NH
HO' ' N NH
y bH OH

Compound 416 Compound 417 \
\ -FN=\ /=N
-F N=\
0 0 0 r= N 0 0 H2 a 0 YYN''5%."04-04-04-0 NH2 0Y--Y\l''' (:)-Vc ii ii i HN __ N OH OH OH 1 - ' N , N
--,--- HO OH OH OH : -- N , N
d bme --' --r-- HO
d ome H2N 0 0, /
H2N -,f0 ' P,-O a /N¨ 0 \h,__Iy0 Ni=N7N,,,f0 HN --õ,0,- 0 cOi_...Nr\r----r-NH
HO' ' N õõ NH

OH a -OH

Compound 418 Compound 419 \
/=N1 ONõ, 0 ,.õ 9 9 H2 9 NH
H a a N OPOPC PO'''''.--\'o'rN
-F "N''' 0 04-C2-1=-o-A-oNH2 HN ,...N OH OH OH
HN -- N OH OH OH HO d y HO
Me"d H2N 0 H2N 0 N¨ 0 a N¨ 0 / / \......u....0 \N
rNH
HO' -.OH N- NH
HO' " 0 Compound 420 Compound 421 Date Recue/Date Received 2023-07-07 \
*N= ON, () 0 0-CpLolFi2_1L0.......,c)...=NN 0 2 y.,,,,ylr,. ..1,,0 j:1,)-c012-jiLo j N
0 0N/ NH iL 0 ,,o....Nyz,V,I,NH2 HN ,N OH OH OH I
: -- , N
HN ,-- N OH OH OH -- -- N , N )--- HO d Ome Nr- HO 0, /
0, / H2N Or H2N 0 N¨ 6 o N¨ 0/ /

.NNO
rNH
HO' -, N õyNH
-u HO' .., 0 OH

Compound 422 Compound 423 \
o 01 2 0 NFI2 HN N OPOPC 0NN?'1fNH2 -P-O-P-OrN , HN ,N OH OH OH -- -- N , N õ--,N
T HO OH OH OH : , N , N
d oMe "--""
"n" HO Ci oMe ''-' H2N 0 / -P,- 6 0 N---N¨ 0 /
, -v¨ 1\ - (:) r,d_..N z Nir-NH
..L---( HO'H N NH
u --HO' -_, 0 O i Compound 424 Compound 425 \
\ -FN=\

0 0 0 0 N NH2 O'yeS7''''' 0 P 0 P 0 P essc:0')::

OY''Y
HN ,-- N OH OH OH ' ' N --, N HN, õ,-- N OH OH
OH ry,,,rNI iN NH2 r HO 0 oMe )--- HO d bMe ""-7 0, / H2N 0 H2N 0 'P...,-/
N¨ 0 /
/
cOje...N ---r\r \'..".0,...N
,ir-NH bH HO' .
Ni.., NH
HO' " 0 OH

Compound 426 Compound 427 \
\ *N /=N
-F N=µ i=N 0 S 0 N
(D,j\I , , .50 ..õ (7) -II -01, _. _iv _ o ,..._or N,NH2 ..y--1N , . 50 .õµ,0 ilz,I 0 II 0 ig 0,......cir NH2 V
HN ,N OH OH OH I
-= =- N , N HN õ. N OH OH OH
(5: =-bmeN N
--,.7"--)--- HO
-,--- HO d oMe -' 0, / H2N 0 H2N 0 'P.,-/
N¨ 0 /

_..NNO
r-NH HO' . Ny., NH
--u HO' -_,H 0 'OH

Compound 428 Compound 429 \
-FN= /=N 0 0 0 S 0 N NH2 0 S 0 i=r,V,yN N Nr,\õi NH2 ----S,,-ON, -. '"µ 0 F' 0 F' 0 F' 0 ....--0-..
g-O-P-0-1g 0 (:) HN õ. N OH OH O
HO H onneN
H2N o d / b I
--- , , N HNN
HO OH OH OH -- -- N , N
0 Me )--- Ci '-' .
H2N 0 "P.,-/ 0 N¨ 0 (3 N¨ 0 /

cOi_..Nr-------\r r-NH
. HO' ' N , NH
u HO' --._,H 0 CH i Compound 430 Compound 431 Date Recue/Date Received 2023-07-07 \
\ *1\1=\
*N=\ /=N 0 , 0 0 0 0 S Oy...,/,NrN,, 13 ii n II ii I\I '5 '"10-1ILO-P-O-P-On'.."NH2 N
y 0 P N P 0 P 0"...'..'. ).'"i=y).-HN _.õ. N OH OH OH -- '= N N HN ,...N
HO OH OH OH - =_ N N
d ome --,.7----,--- HO b. eme O . / H2N o N-cOy.N N 0 r-NH HO' . 'OH
N,T,,, NH
HO' --6H 0 Compound 432 Compound 433 \
\ +N=\ /=N
*N=\

0 0 0 0 /=N 0 0 0 9 N z NH2 N, II H II II NH2 PP
N N h '''0 0 INI P 0 "YeS7 5 0-P-N-P-O-P-0 OH OH OH - -=
HN _.õ. N OH OH OH - = N -,, N HN
-1-----N HO d bme ----"
--r-- HO d "(Dime ----7 o,F,/_ H2N o H2N o 0 N- 6 o N- 0/ / _. rN
, 0 c(Di..Cr o r-NH
N NH
HO'' '-o- H
HO' Compound 434 Compound 435 \ \
-,N=, ,=N =rst¨\
0 0 0 0 0 F=N
0 m NH2 Oyy õ (13 .0-, 9 9 H 9 ,....._a_...N'NH2 , . H
H II II

pOPOPOPO-Nrir 1 HN,, õ...-=N OH OH OH OH =
HN -.--- N __ ) ,,, ,,, ,H . . N -., N r Ho 6 bme -------,--- HO d -Me ----7 0.

H2N O=K'P--,- N¨ 6 o /
/ r i=--N
y0 c0]..NeD
r NH
HO' OH N NH
--r HO' " 0 Compound 436 Compound 437 \ \
* N=\ /=N -,-N=\ 0 if=N

y,../,µNrN, 0 ii ii ii ii ,.........O.,=N Ni),õõ(NH2 C'y'.4 0 . , 0 0 H 0 P 0 P C P 0 P 0 OPOPOPOP-0 Z '' i HN,. ,.......N OH OH OH OH "- N ,, N
HN .--- N OH OH OH O
HO H
ci' "=-orvieN N T HO Ci 'me -,---- ---,/`
0.,pi,_ 0, / H2N o / / 10 Ni=N
/ 1_9j,sNC) rNH
HO ' bH N --, NH
HO' - 0 bH NH2 Compound 438 Compound 439 \ \
0 /,---N

0 v0-A-cH2-A-13-A-cr.....Ø....N ),T,NH2 o 0-17 0 (Lc 17 0 y,,,,N, 0 9 9 ciz 9 9 N
1 HNN OH OH OH OH ,, N , N
HN .--- N OH OH OH OH ci- =.'ome N--'N HO 0 Ome -----"
--,--- HO 0, /
0, / H2N 0 H2N 0 NI¨ 60 0 F=NI
/ /
c(3I_y=NrNr9 \-...i_y.Ny.,, P
rNH
HO N , NH
OH 'I.
bH 9 NH2 Compound 440 Compound 441 Date Recue/Date Received 2023-07-07 \
\ +N=\

Nu, 0 ,,õ 0 0 ci2 0 0 I\l' O A 0 A 0 A
(:) 0.'.-0 N -..N?i----kT . PPC
POPO'''s0'. Ny)(NH2 I HN õ OH OH OH - =- N
O O , N
HN -N OH OH OH OH . - N -, N '''r- HO NH OMe --r HO d oMe ----H2N 0 'P, -N¨ 6 0 N¨ 0 /

,rNH
HO' - N , NH
HO' bH 0 bH i Compound 442 Compound 443 \
\ -,N=\
*N=µ /=N 0 0 0 0 0 /=N
i ON,.. 0 .õ 9 9 9 oy,yN,,04-04-04-0,.........0õ,N NH
S' o I
HN,, _,...N i OH OH OH ---"---0--.NNH2 = =- N , N HN ,....N OH OH OH
re- HO d bme ----1-- HO NH bme --v 0, /
H2N Or('P,-N¨ /N¨

/
cOi....Nr---<\r r NH
. Ho' ' N , NH
HO. --_, 0 OH i uH NH2 Compound 444 Compound 445 \
\ +N=\ /=N
+N=\ /=N I 0 0 0 0 0 0 (,,,,y,,, 0 N , N y i 'OPOPOPO
oN"'5 NH H H H µO-P-0-1L0-1'-Or I
I I I N ,...N 6 O O : .- N
, N
HN ,õ N OH OH OH -= =- N , N HO d bme '--' --,-- HO 6 bme --' 0. / H2N o ( H2N 0 - P,- N¨ 0 N¨ 0 / \ 0 \.11...Nr),õ,f, rNH
HO' ' N , NH
HO';OH 0 OH y Compound 446 Compound 447 \
\
+ +N=\
0 0 0 0 0 /=N
O1\1õ 9 0 9 9 9 9 N NH2 N,,, o II II II

N S l' o l' o l' o N?')'r HN N 6 6H 6H __ N -- -- , N HN õ...N 0 OH
OHNN
HO \'- bme '--' Nr- HO - 0 bme '--' /(3 H2N 0 ( H2N o N¨ HN
N¨ 0 /

cOi_..Nr\r---- \*.õ
vi,_ \ _O Ni=N
N.r0 ,ir-NH
HO' ' N , NH
HO'--., 0 OH y uH NH2 Compound 448 Compound 449 \
0õ _Z N,, 0 ,.µ, 9 9 9 0 Ny,,,r NH2 0,, _Z N,, 0 9 9 9 0 NNH2 y S
T 5 0-P-O-P-O-P-V-"str V i HN,,N 6 OH OH - - N , N HN N OH OH OH
0-= ,bEt ,, N N

1-- HO - \''. --0Me HO
0, /

N¨

N¨ HN / 0 Ni=N
-''o \\cOyNr\----,ir-NH
Hd --_ N , NH
bH OH y Compound 450 Compound 451 Date Recue/Date Received 2023-07-07 \
\ -,1\1=\
0 0 0 0 /=N

-,1\1=\
0 0 0 1=N 0 0 ,õ,õ, ii ii ii NH2 0-P-O-P-O-P-0 V i O-P-O-P-0-1g-0 )-'"Nr OH OH OH
HN __ N OH OH OH -= , N, N HN -- N
-,--- HO d On-Pr ----"
-,--- HO d OEt -'-' 0. / _ H2N o -P,-H2N 0 'P, N¨ 0 /

Nir-NH
u HO' bH ' N .õ NH
H 0' -1_,H 0 i Compound 452 Compound 453 \
\ +1\1=\ /=N
-F 1\1=\ 1=N 0 0 0 0 NNi),,T,NH2 0 0 H yYN'' 5 '''O-P-O-P-O-P-0.--0-µ
N"S .'"Th7)-P-0-1g-0-1g-0 )--"NIr NI 2 I I I HN --N OH OH OH -- == N
N
HN , N OH OH OH -= , N, N )--- HO 6 bi-Pr '-' si-- HO d On-Pr ----7 0. / _ 0, / H2N 0 H2N 0 'P,0 - N¨ O
N¨ 0/ / 0 Ni=N

c5...Nr -Ty, Nr,L,f, 0 rNH
, HO' ' bH N NHi HO' - 0 bH

Compound 454 Compound 455 \
\ *N=-\
0 0 0 /=N
0 1=N\
õ,,,r NH2 0 H2 "Y N': P-0-1LO-P-0 )-.'N
Y--Y-F N1'.50 '''µO-Olg-0-01g-0-1)g-ONIrN
OH OH OH : =/ N
N
HN , N OH OH OH -- -- N ., N 'r- Ho 6 On-Bu "---,¨ HO 0 oi-Pr ''v O. /
O. / H2N 0 -H2N 0 N¨ 6 o /
/
/ r NH 0 N¨ 0 0 /=N
\***,12.õõ, N N?õ,f0 No r' HO' --.-_, uH HO'N NH 0 bH y Compound 456 Compound 457 \
-F NI=\
0 0 0 1=N -FN=\ /=N
NH
50 II II II .).....Nyh,,NH2 0y-cr 0 Nyz,L1,,, 2 I N Ni," 0 ='"0 ')g 0 0Ig 0 (ljg 0 I
HN __ N OH OH OH : -- N ,_ N HN --N OH OH OH
HO 6 On HO
H2N o - P_ , H2N 0 N¨ 0 rNH
HO' HO' OH ' N --,, NH
--;.. 0 OH i Compound 458 Compound 459 *N=-\ 1=N *N=-\/=N

0 0 0 0 0 N z NH2 Oy.-yN,,.5 ii ii ii NH2 Oy ,-4,,N , p.50 F' 0 F' 0 F' HN __ N OH OH OH : -- N ,_ N HN ,... N OH OH OH
(5: --omeN N

HO 6 bm. )--- HO
0, / H2N 0 H2N 0 /
N¨ 0 / 0 /=N

cCI_NrNr \'.."=0,...Ny.),,f, NH
' -õ.
HO' -OH 0 HO' OH N
NHi Compound 460 Compound 461 Date Recue/Date Received 2023-07-07 P
+N=, ON

'5 'Th21-P-O-P-O-P-0 r N NrNH, ON , 0 ,,,,,_ 0 P 0 P 0 P 0'...--(0_rrY)-r NH2 I
HN _._ N OH OH OH : -- N ,_ N HN _ N OH OH OH
)--- HO d bme ----"" 'f--- HO d bme '--' ch. /
H2N o - P,- H2N 0 N
N¨ ¨

/ 0 o/ 0 c_0_tNr\r---- / 0 /=N
\.'y2....Ne r NH
HO' "
bH o HO' ' bH N ,. NH

Compound 462 Compound 463 P o \
,-N=\

0II' 0 F' 0 F' N/=N?''''rN 2 I

rjy,,,,, N,50 ggg_e..s.cOr HN _ N OH OH OH
ci: --omeN N

I 0, /
HN _._ N OH OH OH NNH, : -- N N r-NH 0 s'r-- HO d bme '--' I
/
H2N C3,.Ni=N
if0 N¨ 0 /

c_Oi...N-r-\r HO' = H N ,. NH
b --r ,ir-NH

HO' =-. 0 uH
Compound 464 Compound 465 \
\ +1\1=\ /=N
-FN= /=N 0 0 0 0 9 II II II Y--YN"'II II
0 ig 0 ig 0^-CrY--crNH2 5 H -P -0 H -P-O H or NN , N N HO d ?,),r NH 2 HN _._ N O O O -= HNõ. _.,-N OH OH OH -=
--r bme '--)---- HO d ome _ NiNH o NH 0 N¨

'P, 10 r_ I N¨ 0 /
/
i_oi_..NI=N0 \r\r-- z , .
HO".--_ N ,. NH
HO' ' Compound 466 Compound 467 \
\ -F 1\1=\ /=N

0N ,, 5 0, oMe 0 ,,õ 9 0 N NH2 N. 0 0 p 0 p 0 p rYNH2 0- -0- -0-P-0 "--.."-c- r 7 1 HNõ N OH OH OH , -- N ,. N HN _._ N
'T-- HO OH OH OH
(5' .-b Me N---"-- N
r HO
0,p.._ ----""

N¨ 0 /
/ 0 /=N
%...Nr------NeD \k***-Cy.Ne Nir-NH
..----/ HO' ' N
,. NH
H O. --,_ 0 uN bme i Compound 468 Compound 473 \
\ -FN
-F
N=\ /=N 0 0 0 OY..YN"50 0-1'-0-1LO-P-0 0 N y NH2 I\l''' 0 0 P 0 P 0 P 0'-..--0)- I\IN?NH, HN ,- N OH OH OH I
-= == NI N HN .- HO N OH OH OH d: ,orvie N N
--....---)---Nre HO d bMe --- 0õ/ _ / 0 N¨ 0 N¨ 0 / 0 /=N

c_Oi..NrNr \N.,,e\-õ,f0 ,i7--NH õ . , NH
HO
HO' - 0 On-Pr i bMe NH2 Compound 474 Compound 475 Date Recue/Date Received 2023-07-07 \
\ +N=\
-FN=\
0 0 0 1=N 0 0 0 0 0 NI=N NH2 0 N NH2i'I II ' 0 0 IIN?')'r ON',5(:) '''µO-ILOHLO-IL0'.."--LY V i 0H 6H OH = ,,_ N
N
HN --N OH OH OH , == NI, N HN, N
-1-- Ho c'H2 UMe -y HO d bme ---7 0, , 0, / H2N 0 H2N 0 N¨ 0 N¨ 0 /

ri...NrN \*.õ, , _O rNi\_ ,o Lr yNH
HO' ' N NH
HO'"- 0 bH i un-Pr NH2 Compound 476 Compound 477 \
0 ,., 9 9 N
II

+1\1=\
0 0 0 ')NH2 ')-----Cr'N NI' ' OPOPOPON?'Y
50 'µ"0-1'-0-P-0-A-o OH OH OFI
HN _N OH OH OH i - =-___ N,õ N HNõ _...-N
r HO
Y HO el-12 UM e ---7 0, / H2N 0 C!_.
'bme N N
H2N 0 -P,- N¨ H2d N¨ 0 /
, 0 NO

\r-o yNH
HO' ' bH N NH
HO'u H "--,H 0 i Compound 478 Compound 479 \
-FI\1=\
0 0 0 1=N 0 õ, 0 0 0 0 0 N NH2 0N,,.50 .., NH2 Nr. 'N ''''''0-1LO-lit0-1'-0"'"str N?--117 µ0-1g-O-P-O-P-0 )r7 i O OH OH
HN __N OH OH OH -= , N,õ N HN, N
y HO - .--0MeN
N
--,--- HO H2N 0 H21\1 0 0,p/Cf_ 'we ---' H26 o N¨
(o N¨ /

NO
yNH
HO' ' N ,õ NH
HO' "-;, H0 bH
u y Compound 480 Compound 481 \ \
+1\1=\ 1=N -FN=\ 1=N
(:)N,,,50 ,,õ,,o-olLo-avo-oA-0,0 NN.?,7õTrNH2 0 N N,,, 0 ,., 0 0 .. 0 .. 0 N _ .. NH2 µ0-1'-0-P-0-P-0 HN ,N 0 OH OH -. ' N , N HN --N OH OH
OH I
-= == NI, N
Y HO - OMe ----7 sr HO d oMe ---"
H2N 0 NH Me0 N¨ (0 1 0 HO' --, uH 0 HO'"--, uH 0 Compound 482 Compound 524 \
+1\1=\
0 0 0 /=N \
+1\1=\

50 -"o-Vo-A-o-Vo^-n--"",?---TrNH2 0y.-y..5 j_vo_vg_0,-..-0_,. N/=N
HN ___N OH OH OH -- -- N,õ N
y HO d ome '--' HN ___N OH OH OH
tf' --Om.N IN

HO
H2N 0, /

/ H

i__ y ./7N) N¨ N 0 o \'Cl Tz T o / N¨ NyNH
õ NH /
OH N y HO' " 0 OH

Compound 539 Compound 540 Date Recue/Date Received 2023-07-07 \
.N=\ \

0 /=N NH -FN=\ /=N
--yN.õ5 II II II
Ncµµ0-1-0-1-0-1-0'..ssc 2 0 0 0 C)YYNI,'5o 0 '-0-P-O-P-0-c )-"NrNH2 HN _ N OH OH OH : -- N -., N
Nr HO d ome '-' HN __ N OH OH O
0 HO d ome H -= , N,õ N
, / -,--- '-/
H2N 0,s, HN '0 6 OH H2N
HN' "0 6 OH
\ /=N
\IIII0yN) \
V
r\C) H ,,,rd - N
bH NH
HO' 0 NH2 uH
Compound 541 Compound 542 \
-,N=\ 1=N \

0õ i N50,,c,, II II II ,.........c0.7..õN,NH2 -FN=\

(:)-P-O-P-O-P-0 0 5 ,,õ 1,1 II II
N''' o-P-o-p-o-p-O"c HN _ N 113 OH OH , , NI, N
Nr HO d "me '''r HN --N B_ I-0, / Nr HO 0 OMe H2N Me0 6 OH H2N Me0 / OH

\*...õc0j...rio V
\.....µCy= 6NNir-NH
Hd .--_ N,, NH
OH y HO' OH 0 Compound 543 Compound 544 \
/=N \
(:),y+N=\N,50 ,.,,s Op, 0 II 0 O 0 +1\1=\ /=N
0 N 7 NH2 (D,y,,50 ,,,,s_Olit0_0v0_0v0 0 N y NH2 HN, _ N OH OH OH I
: -- N N i y HO d 'me --' HN .__N OH OH OH : =-, N,,,,,,N
'7--- HO d OMe H2N Me0 0, /
0 H2N Me0 "Põ-O
,c, o ,--_,..õ0 NO
Nr-f \----0--N,,,,_NH
HO, N NH
OH i HO' " 0 NH2 bH
Compound 545 Compound 546 \
-FN=\
0 0 0 -FN=\ /=N
0 II:' 0 P 0 II:' s N z NH2 0 0 0 HN --N OH OH OH I
-= , N ,õ N (:) '-0-P-O-P-S ."INH2 N
)--- HO d ome HN --N OH OH OH N,,,N
0- ' Nr HO 0 OMe H2N Me 6 o H2N Me0 6 o N?,e3 z \.....µCy= 6NNir-NH
HO' % N, NH
bH i HO' --õ 0 NH2 uH
Compound 547 Compound 548 \
-FN=\ /=N \
0 0 0 0 0 0 N NH2 +1\1=\ /=N

N 1\h" .'"Ci POPOP 0 / 1 0 0 H .5-- OH OH OH ---.7.Q:. Nir\-TI o,ryNI 04-04-04-0,=.-0,.y,rNH, ''' ')17---Cre-Ny- HO 6 brvie'"' HN __ N OH OH OH : , N,õ N
0, / )--- HO d bMe ----'' H2N Me0 ,S,0 1-12N Me0 HN .'0 HN
Z
\***Ty= 6-rNH
HO' % N --,, NH
OH i HO' OH 0 Compound 549 Compound 550 Date Recue/Date Received 2023-07-07 \
\
oy,,,'"=\,,,,.. 0 ..õ. 01, 0 ::), 0 01, 0,....._0_, /=N -,N=\
NH
0 N,,,c).--i 2 0 0 0 0 /=N
I I I i NH2 o-A-o-Vo-Vo''.--c HN õ, N OH OH OH = , N
)--- HO bH2 ome -----' HN -- N OH OH OH . == N , N
H2N Me0 (:)--/S/,0 HO
H2N Me0 HN C:0H 2 bme ------' HN
Ni=N, 0 Nef \***T2"6-Nir-NH
HO' ' bH N NH
i HO' " 0 Compound 551 Compound 552 \
.N=\
0 0 0 +1\1=\ 1=N
I\l''' 'µO 1" 0 II0 P 0 0 N , NH2 0 0 0 HN ,,.,N OH OH OH I 5 '-0-P-O-P-0 i T HO HN __ N OH OH OH -- =- N ..,, N
s,p<2'l 'bme N'-'.- N
'7--- HO d bme '--' H2N Me /
(50 H2N Me0 SC ,-6 o \c0y.N/=N, ,O 0 HO" f-=No Nr,r `..---o--6-rNH
'_ N --,, NH m OH i NH2 uH 0 Compound 553 Compound 554 \ \
-F\r0 + N=\

Oyõ,c(N,,,50 II II II
'yeNCr, 'N'.5 ''''O-P-O-P-O-P-00µrN ,--NH N 0-P -0-P
-0 -P-0 Nr-N
HN __ N OH OH OH // HN -- N OH OH OH
'7--- HO d OMe Nr- HO d OMe O. O. /
H2N Me0 -1', ,- H2N Me0 - ID,-(5 \......c0,..rN, ,0 \.....,c0y1,171\0 "OH
N NH ..
OH
HO' ' N , NH
I

Compound 555 Compound 556 \
0 0 0 +1\1=\

0YYN''' 0 P 0 l' 0 l' 0 0 N NH2 ONT .,,,, II II II
I I I I N 0 -p -0 -P -0 -P-0'-..--0-''N'Ir HN _ N BH OH OH
_ 3 -. .= N --,, N
)--- HO HN _ N BH OH OH
_ 3 -. .-NI , N
0,Fe Ome '--' Nr HO Ci bMe ---7 H2N AcHN
(5 "OH H2N AcHN

c0"..riq,_ ,0 0 --__H N N
NH rNH
HO' -- 0 Compound 557 Compound 558 \

N NI' S P 0 P 0 1' 0 Z i 0 0 0 HN OH .5-- OH OH OH ?PT, 'ell N,,,5- ,,,s_11: -0_ II.: -0-11: -0,-,\--0NT?õ).,N
r HO d bme = "-' HNõ. .õ....- N OH OH OH
HO
H2N AcHN
(5 PO H2N AcHN (:). 'orvie N N

Nr Nir-NH
HO' ' N --,, NH
-01-1 i HO. "'OH

Compound 559 Compound 560 Date Recue/Date Received 2023-07-07 \
+1\1=\
..õ,(j_Ljvc,vs0e,..Nyrz i NH2 -,N=\ /=N

04_04_04_s,.......c0)_,..NNH2 HN -- N OH OH OH : ' 'T--- HO d oMe ---7 HN -- N OH OH OH
N
HO 0 OMe H2N AcHN
do H2N AcHN

oyN/710 0 V
Nir--NH
N --õ NH
'OH i HO' -- 0 OH

Compound 561 Compound 562 \
-FN=\ \
0 0 0 0 /=N
Ito_lito_,_0,0....0 Nryõ(Nyi , NI-12 0,'- "NI .µõ0Lo_0g01L0,...._0_,..0 N

HN ,... N i OH OH OH : --HO d -Me ---7 HN __ N OH OH OH
(5: =-bmeN N
----7"--0, / Nr"- HO
H2N AcHN HN 0 HO AcHN

r\ITIO 0 V
rNH
N --õ NH
'OHy HO' -- 0 OH

Compound 563 Compound 564 \
-FN=\ /=N \
(3. c 0_,V_o_ito_9p_0,-...._(.7,...y., ,, r NH2 +1\1=\
0vo_pg01gpg_c),......_c HN ,... N i OH OH OH - --)--- HO 6H 2 'OM e - - - -7 HN -- N OH OH OH
- == N
0, / )--- HO 0:0H2 bMe HN '---7 H2N AcHN 0 H2N AcHN
HN
\..,fi....N/70 0 C' y.Nr V
Nir-NH
N -, NH
bH i HO' - 0 OH

Compound 565 Compound 566 \
-FN=\

II II II
0 N , NH2 OyYNI'' 0 ''''OPOPOPO oyS,+ N=\N,..50 .µõcr_ILo_pg01L0,......0_,..0 rrN?,_TrN NH2 HN , N OH OH OH I
: -- N,,, N
HO Me HN __ N OH OH OH : =- N N
S!_ ''-' Nr"- HO d bMe ---7 H2N AcHN sõ,,,/ _ 6 o H2N AcHN

V
orNH
HO' "-OH NyNI-1 HO' NH2 'OH
Compound 567 Compound 568 \ \
-F N=\ ----/-0 + N=\ (--."---)._-NH2 0 0,)õ,,crN50 ,.õ0-01,-04-04-0,......c0r,,Nr C)---Yr\l'"5 ='µµO IV 0 IV 0 IV 0'....- )--.1\1,-Nhl HN __ N OH OH OH ii HN ,... N OH OH OH - -- 0 )--- HO O bMe '7--- HO 6 OMe 0õp/ _ H2N AcHN H2N AcHN
NTro c:Oi_AN/70 Z V
A-----( HO' OH
N -, NH 'OH N , NH
"
i i Compound 569 Compound 570 Date Recue/Date Received 2023-07-07 \ \

(:),^ 1\i''' YyNH, 0 /=N\ NH, or\l'5o O-P-O-P-O-P-0",(---r7 i i , 1 HN ,N B H3 OH OH -- =-, N , N
-,- HO 3 0 HO 0 OMe HN ,N BH OH OH d bme _ N , N
. , --,-- ----7 H2N 0 - I., O. /

N¨ 0 N¨ 6 / OH
?,e , 0 Z
HO' :0E1 NyNH ,ir-NH
HO' -- 0 Compound 571 Compound 572 \
-FN=\
O o o /=N \
(:)--S,N1''.5 "'s-Vo-Vo-Vo 0 N z NH, +1\1=\

HN ,... N OH OH OH I
: == N , N oYYN'' 5 S-ILO-P-O-P-ON N?r NH2 HO d Orme ---' HN N OH OH OH
ci: =-"onneN N
0, / --,-- HO -,7---H2N 0 ' P,- O. /
/ 0 H2N 0 -P,-N¨ 0 N¨ 6 \i,e / 0 c r 0_7_..r V
yNH
N yNH
-OH HO' -- 0 OH

Compound 573 Compound 574 \
+1\1=\ /=N
\
0 J=N
Yr\i''S Vs^c ri\IN?INH2 0 0 0 0 ,--y,5 õ,,04_04_0_vs,...._L).... Ny-y y i NH2 HN ._- N = OH OH OH - = N , N
'''f--- HO d 'OMe d bme ----H2N o / o H2N o -P,-N¨ 0 / 0 / N¨ 0 / rr V
\****fy. yNH
HO' .-- N ---- NH
OH i HO' ' 0 -OH

Compound 575 Compound 576 \
-FN=\ /=N \
0 0 0 +1\1=\
OYS'N''' 0 = '-0-1'-0-1L0 0 N 7 NH, 0 0 0 0 HN ,... N OH OH OH I
: -- N , N II II II
y,yN,.5 0-P-0-p_0-P-0õ......0,... N,yN NH, -,-- HO d -Me ----7 HN ,N OH OH OH '-, NN
HO 0 OMe HN/SO 0,s, N¨ H2N 0 HN

N¨

\\ty.0 NTi 1),i õ.fp / 0 rr V
,ir-NH
HO' "s, uH NyNH
HO' , 0 OH

Compound 577 Compound 578 \
-FN=\

(jr\i''' 0IILO'as--c rNNINH2 ON,, 50 vo_vo_A_0,-...._c_)....
NN?,,irNH2 HN --1\1 = OH OH OH = N , N
'7-"-- HO C-H2 bme ----"' HN N OH OH
OH - ==,_ N N
HO CH 2 UMe -,7---H2N 0 S,(3 N¨ HN O
N¨ HN
/
\Ni=1* , 0 /
yNH
N , NH
'OH i HO' u .=,..,H 0 Compound 579 Compound 580 Date Recue/Date Received 2023-07-07 \ \

i=0 C) 1\i'' 0 NH, o--S/N'. (:) N
'''' O-PO--PO-'.....-0'' 2 HN ,N OH OH OH N, N
-,--- HO d bMe ----"" HN ,N HO 6 ome OH OH
OH N, N
Sõ,,,,_ Y --.' o / o H2N o N¨

/N¨ 6 H2N o ....,coyN/ , HO' .bEi NyNH
HO' "..0 0 Compound 581 Compound 582 \ \
-FN=\
0 0 0 0 Nr----\r +N=\
0 0 0 0 n--Oy--cr,N,,,50 ,,,µ..., II II II
N 0-P-O-P-O-P-o'..sc '1µ.6.-)r-NH N
C)1\i'.5o "0-P-O-P-O-P-0--I/
HN ,N OH OH OH HN -N OH OH OH
Nr HO d OMe 'sr HO 6 OMe H2N 0 H2N o -P,-N¨ 0 N¨ 0 / /
\\cOy Ni=Nr\o Z /
HO' O
.--_H N , NH bH N, NH
i y Compound 583 Compound 584 \
-,N=\
*1\1=\
oy=-õcrõNc, ,.,,o L j cy,......c HyrNH2 0 0 0 0 /=N
5(:)P-0-1L0 II
-1-0'-....-\'' =7....yNH2 HN _ N ) OH OH OH : == N IN
y HO d "F "' HN --N OH OH OH : ' N, N
o, / )--- HO di -F
H2N Me0 -I.,- 0, /
6 o H2N Me0 -P,-O
\rj...N?1,e y \iy.-Nir-NH
HO" ' N , NH
'OH y HO' " 0 NH2 bH
Compound 599 Compound 600 \
*1\1=\ /=N \
9 9 9 *1\1=\

01-0-17-01-0 NN?'NTrNH2II o yyN,,50 (:)_-(:)_,L0--(:)......_c0)_...N/rN iNH2 HN --N OH OH OH '. ' N, N
Nr HO di 'F "-- HN --N OH OH OHNN
0,,,p,_ Nr HO di -F
H2N AcHN 0, /
6 o H2N AcHN -P,-C5,.N/7N)0 T C y.rr z T
y HOõNH
N, NH
OH y - OH0 Compound 601 Compound 602 \
-FN=\
0 0 0 /=N \
0 N,V,iNH2 CPYYN'''50 ''"0-P-O-P-O-P-V.---0-' 0 0 0 OyS/N,,50 04-04-04-0,.....c0)_...N
HN ,N OH OH OH I
-= , NI, N
Nr HO 6 "F ---' HN --N OH OH OH -=
, NI, N
0, / Nr HO di -F
H2N 0 -P,- /

0, N¨ 0 / N¨ 6 o c j...N/7r\fo / o Nr z Nir--NH
HO" .--_ N , NH
OH y HO' -- 0 OH

Compound 603 Compound 604 Date Recue/Date Received 2023-07-07 \
+1\1=\
1=N
0 0 0 +1\1=\
NH, ,..õ II II II 0 0 0 (DY''Y 5 Op0p0p0'..'stal..Y')'r s .,,,...õ II II II
, ON NHy 2 HN õ..N OH OH OH
: -- N., N
Nr-- HO HN ,N OH OH O
ci H :
=,, N N
H2N Me0 "P Nr HO .- OMe O. / 6 1 6 H2N Me0 "P..- OMe a coy.Ni=N,_ ,0 \*i_y6NyNH
HO' ' N,õ NH
'OH ---r HO' 'OH 0 Compound 627 Compound 628 \
+1\1=\ 1 0 0 0 \
, ,.õ II II II 0 N=N?,rN NH2 -F1\1=\
()N"5 OPOPOPO 0 0 0 0 /=N
HN ,,-N OH OH OH
6 HN N . -- N., N

)-µ1\INi '7--- HO õ _,...-- O O
HO H H OH
H2N AcHN "Põ,- OMe 0. / 6 i d 6 H21\1 AcHN '1...õ- OMe \....,c0,..rN, ,0 0 c()_ Nr`f Nir-NH
HO" ' N., NH
'OH ---r 'OH 0 Compound 629 Compound 630 \

0 .,,,..õ II II II -O' N NH2 0 0 0 IDY--^ YNI''.5__ 0 P 0 P 0 P 0'...-'N?'''r Y.-YN"5 ''µO P 0 P 0 P a NY')'rNH2 HN ..,-N H H H -= =- 1\1,, N
)--- HO d OMe O O O --' HN ,,-N HO OH
OH OH '. ' oMe NI, N
d H2N 0o 6 H2N

HN
C5,.NI=N,0 \ \\cOyNr-r , \
Hcf- bH N, NH ,ir-NH
--r Hd " 0 NH2 'OH
Compound 631 Compound 632 \ + \ +
N1=\

r=N
0 0 0 0 Nr\l',. a O A 0 A 0 i4 O 0 0 N , NH2 0 ., II II II
Y--YN''5 ' OPOPOPO'-..--CyNO
' 1 HN _--N OH OH OH -= , N, N HN, õ,...N OH OH OH
)--- HO cL g 'OMe' r HO 0 / d 'OMe --r H2N -P, - H2N NH2 cN/=Nv 0 iN---\\2 C(Dy.N11:=N3, 0 \\--0 y T
HO' ' -OH N 'OH ., NH HO" - NyNH

Compound 633 Compound 634 \
+1\1=\
0 0 0 /=N \
a P 0 P 0 P

HN ,-N OH OH OH 1 : , N,õ N 0:NI-51V0 1=zr' J J
T HO d bme H O OH OH -- , NI., N
HO d OMe "
H2N N3 0 , /
6 o H2N N3 ' P, -\
6 o ....,c0yrN, 0 0 Nr`f 'OHNyNH )r-NH
Hd ."-oH 0 Compound 635 Compound 636 Date Recue/Date Received 2023-07-07 \
-, N=\
0 0 0 0 0 0 -,N=\ /=N
P 0 P 0 P 0'-'s-Lr NIN?r NH, 0 0 0 0 0 H'IriCr OH OH OH : .- N ., N ol\l''' P 0 P
0 P NN?rNH2 i Nr- Me0 HN ,N OH OH OH , , 0, p ome ---, Nr- Me0 d bme "-' H2N Me0 'P,-0/ H2N Me0 6 o 0..1,1/=Ni, , 0 \\Cyr .,L/ Nef ,ir-NH
Hd - N .õ NH
'OH i Hd --=_. 0 NH2 'OH
Compound 637 Compound 638 \
*N=-\ 1=N \
0 0 0 +N=\ i=1\1 F' 0 F' 0 F' 0 0 N z NH2 ttto NH2 HN, _ N OH OH OH I
: , -1-- HO d Ome '-- HN ,... NJ OH OH OH : , 0õp/_ '7--- HO d Ome "-' 0 d 0 H2N HN -P,-¨N
\c0),.Ni=r N,_ ,0 0 6 o \ ¨N
-OH
N` \
N NNH ,ir-NH
Hd --itm 0 Compound 639 Compound 640 \
-FN=\ 1=N \
-FN=\ /=N
o......--=õc17N,,, ..,,,,0 IV 0 IV 0 IV 0 NH2 HN ,... N OH OH OH i ' ' N , N ON'.5 IVO IVO II
0 I\IN?NH2 I
Me0 d bme -----"" HN ,N OH OH OH : , 'Nr- Me0 d bMe ---7 H2N HN 0, /

\.....c0yrN, 0 0 \y)y.r\
Ne---f Hd. N .õ NH ,ir-NH
'OH i HO' ' -OH

Compound 641 Compound 642 \
-,N=\ i= N \
0 0 0 -F N=\ /=N
(31\1 '5 Th3 P 0 P 0 II 0 N z NH2 0 0 0 0 ,... I
-= -- N ., N y-L,sr,Ns ..,,, II II II

i 'r HO d bme HN N OH OH OH '--' HN, N OH OH OH -. -- N , N
0, / y HO Ci oMe ----'' H2N 0 -P,- 0õp/_ HN¨ 0 0 H2N 0 Ni HN-0 \ 6 o 0 N-r¨Nro Ne- h-c) ---,ir-NH
Hd ' N .õy NH
'OH HO' 'O 0 Compound 643 Compound 644 \
-FN=\ 1=N \

c:Ii\l''' 'µO P 0 P 0 P 0'- .... r I\IN? NH

HN ,... N Me OH OH OH ' ' N , N N1'.5 '''µO-P-O-P-O-P-00-"NrNH2 )--- () d bme ----' HN ,... N OH OH OH -. --0õp/_ -7-- Me0 H2N o 0, /

/ o H2N 0 / o \rN, (2, , \ 0 \cOje..N
Ne HO' ' N,, NH rNH
OH i Hd - 0 Compound 645 Compound 646 Date Recue/Date Received 2023-07-07 \
-,1\1=\
5, 0_10:0z._0_,..,_c-0,7_,,NN?õ11,NH
,õ,, II II II +N=\ i=N NH, HN N OH OH OH -- " N, N 2 (Dri\j',5 ''''(:)-(:)V0-0V0-01Loco)-.'Y''r, i )--- HO d bme --' HN _..N OH OH OH
, --,--- HO
H2N HN _0 (31=',-0 000_ bme O -- \_ -ss'(:) o \_ o yNH
HO' ' N , NH
OH 1 HO' bH

Compound 647 Compound 648 \
\
0 0 0 /=N
+N=\
S '''µO-P-O-P-O-P-0 0 HN --N OH OH OH I
-- " N., N N1,,.5 ..0,0_01Ito_Lo_Lo,......_c(D),...Ni=NrN
)--- HO d bme ------" HN ,N OH OH OH
0õK _ -7- HO

-sS 6 o H2N HN \ _0 0"
Nl ,õ 0 i=N\_ N¨f ,---s:),. d 0 Nr N, NH
OH i O H -OH
NH2 ' Compound 649 Compound 650 \
\
-F1\1=\ /=N
, , ,.....coN../ N +N=\

N''.50 0 0 ='µµ -Y-'1rNIH2 ONi,,50 0 ,,µµ(:)-111-0-(,1-01-0 II

HN ,N OH OH OH -- '= N, N
"n-HO d bme --' HN - HO __N OH OH OH - -, N, N
O. / -,-- 0 OMe ----"
H2N HN, _0 0õ,,,/ _ -S' 0 / 0 0" \ -sS--(:) \¨F 0 y-NH
HO" ' N , NH
OH i HO' -OH
NH, Compound 651 Compound 652 \
/¨_N \
1õ),Nri=\+ ,.,,,,., 0 0 0 0-P-0-1g-O-P-0 V i HN ,N 5 '' OH OH OH -- " N., N oN5() OH OH OH 0..,pz.-i " N, N
)--- HO 0,Ft bme ' HN --N
' i 7"- HO oMe ----.-H2N HN _0 / 0 H2N HNs _0 0" -S \ ' 0 \
\ri* ,0 0" \ 0 \
yNH
H0. NH
OH ---r HO. bH 0 Compound 653 Compound 654 \
\
N NH2 +1\1=\
0 0 0 0 /=N
(31\i 0 0 0 0 'Thp A 0 P 0 A 0 50 _ii ii ii õ........_0,..N,,?-õ,,. T,NH2 I
HN ..--N OH OH OH 0 1-0-17-01-0 HO 0 i )--- HO d "ome -- HN --N OH OH OH -- -- N, N
, -0Me H2N Oo -P,-6 o H2N oo O
HN
N
NH
Nrrr\i'Y HN
Hd OH

\4*-1Cy NH
HO' ' 0 r OH

Compound 655 Compound 656 Date Recue/Date Received 2023-07-07 \ \
+N=\
0 0 0 0 0 0 0 0 a Ni=N NH2 N , ,õµ,õ ii ii ii crY'YN",0."µO P 0 P 0 P (D N?'''cr NH2 c:IN '5 0-P-O-P-O-P-0 OH OH OH , -- N , N HNõ _,N OH OH OH , -- N , N
r HO' r HO
0õp/!_ bMe me H2N o H2N o HN
H \....c_OyN/7 N1 NH

d ."-aH Z

HO' .. u "., H0 Compound 657 Compound 658 \ \
+N=\
0 0 0 0 ,-N=\ /=N

'."0 P 0 P 0 P N .õ, ii ii ii N
i Y--YN'''5 0-P-O-P-O-P-0 HN ,N OH OH OH HNõ -- N OH OH OH
'Tee HO d bme --' r HO d bme ----"--o, / o- /
H2N C)o -P,- H2N 0 HN 0 HN 5...Nr-----<\r 6 Hd ' OH Nrr-N,,,r,NH
NH
H
NH2HO'OH

Compound 659 Compound 660 \
-,N=\
0 0 0 0 1=N \
-F N=\ /=N
(:)1\i' c 0 .'"0-1'-0-1'-0-1'-0,-.....0,NNH2 0 0 0 ONI'C .'" 0-P-O-P-O-P-0'-.---n''NNH2 HNN i OH OH OH : , N ---, N
T HO d bme '--' HN,,,'N i OH OH OH
O. , r HO 0, p bme ----H2N HN R.
(:) 0 0 H2N HN

(C)_.N1----(C) Z
Hd ' , NH
OH N i Z. Hd.L----( OH r-NH

Compound 661 Compound 662 \ \
+N=\
0 0 0 0 -F 1\1=\
0 0 0 1=N

NI, (Dr\l'.5 'ThD-1'-0-1'-0-1LO''ssc )-'"NrTi 5 HNõ -- N OH OH OH : -- N , N HN __ N OH OH OH
r HO C2 bme )---- HO
H2N HN 0,p/_ '--' H2N HN O. /

c__Oi_..N/710 Z
Hd ' OH N , NH
'"-r Zi\ \.....-Cy N
HO'.-- OH 0 Compound 663 Compound 664 \ \
*N=-\ 1=N +N=-\ /=N1 0N,,.50 ..0,,0_01L0_01L0_01L0_,.....c (Dr N NH2 0 N
Z ON,, ''''of:Lo-LILo^-0---I
HN .-- N OH OH OH I
-. ' N , N HN .,- N OH OH OH
)---- HO d bme -----" Nre HO.--0 m e N ---"--' N

H c__O__tN
(3 Z
d ' , OH N NH i H
NH2 6HO'õ. OH t-NH
Compound 665 Compound 666 Date Recue/Date Received 2023-07-07 \
+1\1=II II II
0 0 0 /=N \
O-P-O-P-O-P-0 0 N , NH, -,N=\
0 0 0 o /=N

HN _ N OH OH OH I
- = O? o4-o4-o-Vo^-c -"N i )--- HO d bme -----'' HN ,...TN i OH OH
OH - = N'N\--11-,,õ.
0,,,,,_ --r- HO d bme 0 d o H2N

HN

HN
c5 \..,c0i....N/711,0 0 _.r----\r---\ HN
7 \
NNH
HO' - N NH
0H i Hd , 0 OH

Compound 667 Compound 668 \
\
-F1\1=\

0 1,1/=N NH2 -FN=\
,µ- II II II 0 0 0 0õ,N,,,y 0-p-o-p-o-p_o_,-...-_\, .7......),,,,),, r õ a 1=N

N1 5o Vo-Vo-P-0'-..--0-'NN?
HN --N OH OH OH - __ = N,õ N OH OH OH
'7--- HO d bme -----" HN __N - =
N N
, )--- HO d bme 0 '--' H2N HN 'P/ ,- H2N HN 0, /
HN
cOy.N1/7 7,0 HN
N , bH NH
i OH

Compound 669 Compound 670 \
\
+1\1=\
0 0 0 /=N
-FN=\

YS'N'5 µO-P-O-P-0-1LeAs-C1'N 7 i NH2 OY--YN''5C) '" 0-P-O-P-O-P-0 )-..'N
NO 7 H, HN _ N OH OH OFI - = NI, N HN --N OH OH OH --N ,, N
Nr HO d bme -----"
HO

0,11!_ 'OMe HN \...,c0).....Nrie HN

-õ. bH NHi (3 Hd --.--, uhlr Compound 671 Compound 672 Another aspect relates to use of the above-mentioned compound as a co-transcription reagent for RNA
capping in vitro.
Another aspect relates to an RNA molecule, comprising the above-mentioned compound as a cap structure or a cap structure fragment.
Another aspect relates to RNA molecule that can be used as a mRNA vaccine, or can be used as RNA
medicament, or can be used in cell therapy of precision medicine.
Another aspect relates to a pharmaceutical composition, comprising the above-mentioned RNA
molecule, and a pharmaceutically acceptable carrier.
Another aspect relates to a method of synthesizing the above-mentioned RNA
molecule, comprising the steps of:
co-incubating the above-mentioned compound and a polynucleotide template, and transcribing the template.
Another aspect relates to a transcription reaction system for RNA capping, comprising a polynucleotide template, the above-mentioned compound, NTPs, and RNA polymerases.
Date Recue/Date Received 2023-07-07 Compared to the prior art, the present invention has the following advantages:
Compounds of the present invention for RNA capping can be used as a primer for initiating mRNA
capping and present good capping efficiency, and the capped mRNA exhibits increased expression. The cost will significantly decrease when using compounds as provided herein to capping RNA, thus indicating a broad potential for their application.
BRIEF DESCRIPTION
Figure 1 depicts luminescence units of luciferase expressed by different capped luciferase mRNA in Examples DETAILED DESCRIPTION
In order to gain a better understanding of the present invention, the present invention is described more fully below with reference to the relevant figures. Preferred examples of the present invention are provided in the figures. However, the present invention can be implemented in many different forms and is not limited to the examples described herein. Rather, these examples are provided for the purpose of providing a more thorough and comprehensive understanding of the content disclosed in the present invention.
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one skilled in the conventional art belonging to the technical field of the present invention. The terms used herein in the specification of the present invention are for the purpose of describing specific examples only and are not intended to limit the present invention.
Terms:
Pyrimidine base includes but not limited to uracil, thymine, cytosine, 5-methylcystein, 5-fluorouracil, 5-fluorocytosine, et cetera.
Purine derivative includes but not limited to adenine, guanine, 6-N-methyladenine, 6-N,N-dimethyladenine, 2-N-methylguanine, 2-N,N,-dimethylguanine, et cetera.
The term" ............................................................. , in each instance, is a single bond or a double bond" means that such bond structure is a chemical bond, and specifically a single bond, or a double bond. For example, "-X4-, in each instance, is a single bond or a double bond" means that when optional -X4- is a single bond or a double bond, the parent moiety of formula I is a five-membered ring, the groups flanking X4 are directly connected with each other.

Date Recue/Date Received 2023-07-07 The term "form a ring by a chemical bond" refers to "connect two groups together to form a ring structure by carbon-carbon bond, carbon-oxygen bond, carbon-nitrogen bond, carbon-sulfur bond, et cetera", with the corresponding group reduced by 1 to 2 hydrogen atoms if necessary.
"Stereoisomers" refer to compounds that have the same formula but differ in the orientation of their atoms or groups in space. The stereoisomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometrical isomers (cis/trans isomers), atropisomers, etc.
Any asymmetric atoms (e.g., carbon, etc.) of a compound disclosed herein can exist in racemic or enantiomerically enriched form, such as (R)-configuration, (S)-configuration, or (R, S)-configuration. In some examples, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in the (R)-configuration or (S)-configuration.
In general, the term "substituted" means that one or more hydrogen atoms in a given structure are replaced by a specified substituent. Unless otherwise stated, one substituted group can have a substituent at each substitutable position of the group. When more than one position in the given structural formula can be substituted by one or more substituents selected from a specific group, then the substituents can be substituted at each position with the same or different substitutions.
The term "each of ... is independently selected from ..." should be understood in a broad sense. It may mean that specific options expressed with the same symbol in different groups do not affect each other, and it also may mean that specific options expressed with the same symbol in the same group do not affect each other.
In each part of the description of the present invention, the substituents of the compounds disclosed in the present invention are disclosed according to the type or scope of the group. In particular, the present invention includes each independent sub-combination of each member of the type and scope of these groups.
For example, the term "Cis alkyl" specifically refers to independently disclosed methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl.
In each part of the description of the present invention, the term linking substituent is described. When the structure clearly needs a linking group, the Markush variables listed for the group should be understood as the linking group. For example, if the structure requires a linking group and the Markush group definition Date Recue/Date Received 2023-07-07 for the variable lists "alkyl" or "aryl", it should be understood that the "alkyl" or "aryl" respectively represents a linked alkylene group or arylene group.
The term "alkyl" or "alkyl group" used herein means a saturated linear or branched monovalent hydrocarbon group, wherein the alkyl group may be optionally substituted with one or more substituents described herein. The alkyl group may be optionally substituted with one or more substituents described herein.
Examples of the alkyl group include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), n-propyl (n-Pr, -CH2CH2CH3), isopropyl (i-Pr, -CH(CH3)2), n-butyl (n-Bu, -CH2CH2CH2CH3), isobutyl (i-Bu, -CH2CH(CH3)2), sec-butyl (s-Bu, -CH(CH3) CH2CH3), tert-butyl (t-Bu, -C(CH3)3), n-pentyl (-CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), n-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3 -methy1-2-pentyl (-CH(CH 3)CH
(CH3)CH2CH3), 4-methyl-2-pentyl (-CH (CH3)CH2CH(C H3)2), 3 -methyl- 3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl- 3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethy1-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethy1-2-butyl (-CH(CH3)C(CH3)3), n-heptyl, n-octyl, etc.
The term "alkenyl" means a linear or branched monovalent hydrocarbyl group containing 2 to 30 carbon atoms, wherein there is at least one unsaturation point, that is, a carbon-carbon sp2 double bond, which includes "cis" and "trans" configurations, or "E" and "Z" configurations.
Examples of alkenyl group include, but are not limited to, ethenyl (-CH=CH2), propenyl (-CH2CH=CH2), etc. The alkenyl group may be optionally substituted with one or more substituents described herein.
The term "alkynyl" means at least one unsaturation point, that is, a carbon-carbon sp triple bond.
Examples of alkynyl group include, but are not limited to, ethynyl (-CCH), propargyl (-CH2CCH), 1-propynyl (-CC-CH3), etc. The alkynyl group may be optionally substituted with one or more substituents described herein.
The term "cycloalkyl" used herein, unless otherwise specified, refers to a monovalent saturated or partially unsaturated (but not aromatic) monocyclic or polycyclic hydrocarbon.
In some examples, the cycloalkyl group may be a bridged or unbridged, spiro cyclic or non-spiro cyclic, and/or fused or non-fused bicyclic. In some examples, the cycloalkyl group includes 3 to 10 carbon atoms, i.e. C3 to C10 cycloalkyl. In Date Recue/Date Received 2023-07-07 some examples, the cycloalkyl group has 3 to 15 (C3_15), 3 to 10 (C3_10), or 3 to 7 (C3_7) carbon atoms. In some examples, the cycloalkyl group is monocyclic or bicyclic. In some examples, the cycloalkyl group is monocyclic. In some examples, the cycloalkyl group is bicyclic. In some examples, the cycloalkyl group is tricyclic. In some examples, the cycloalkyl group is fully saturated. In some examples, the cycloalkyl group is partially saturated. In some examples, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, decahydronaphthyl, or adamantyl. When a cycloalkyl group is substituted, it can be on any ring, that is, on any aromatic or non-aromatic ring contained by the cycloalkyl group, and it is independently substituted with one or more substituents described herein.
The term "haloalkyl" refers to alkyl with at least one of H substituted by a halogen, wherein the halogen is at least one or more selected from a group consisted of F, Cl, Br, or I.
The term "alkylamino" refers to amino with at least one of H substituted by alkyl.
The terms "heterocyclyl" and "heterocycle" are used interchangeably herein, and unless otherwise specified, they refer to a monovalent monocyclic non-aromatic ring system and/or polycyclic ring system containing at least one non-aromatic ring; wherein the non-aromatic monocyclic atoms comprise one or more heteroatoms (in some examples, there being 1, 2, 3, or 4 heteroatoms) independently selected from 0, S(0)0_ 2 and N, and the remaining ring atoms are all carbon atoms; and wherein the ring atoms in the polycyclic ring system comprise one or more heteroatoms (in some examples, there being 1, 2, 3, or 4 heteroatoms) independently selected from 0, S(0)0_2 and N, and the remaining ring atoms are all carbon atoms. In some examples, the heterocyclyl contains 1 or 2 heteroatoms, which are nitrogen atoms. In some examples, the heterocyclyl is polycyclic and contains one heteroatom in a non-aromatic ring, or contains one heteroatom in an aromatic ring, or contains two heteroatoms in an aromatic ring, or contains two heteroatoms, one an aromatic ring and the other in a non-aromatic ring. In some examples, the heterocyclyl group has 3 to 20, 3 to 15, 3 to 10, 3 to 8, 4 to 7, or 5 to 6 ring atoms. In some examples, the heterocyclyl group is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system. In some examples, the heterocyclyl group may be a bridged or unbridged, spiro cyclic or non-spiro cyclic, and/or fused or non-fused bicyclic. One or more nitrogen atoms and sulfur atoms can be optionally oxidized, and one or more nitrogen atoms can be optionally quaternized, and one or more carbon atoms can be optionally substituted with 0 . Some rings may be partially or fully saturated, or aromatic, provided that the heterocycle is not fully aromatic.
The monocyclic heterocycle and polycyclic heterocycle may be connected to the main structure at any heteroatoms or carbon atoms that result Date Recue/Date Received 2023-07-07 in a steady compound. The polycyclic heterocyclyl can be connected to the main structure through any ring, including any aromatic or non-aromatic ring, regardless of whether the ring contains a heteroatom or not. In some examples, the heterocyclyl is a "heterocycloalkyl group", which is 1) a saturated or partially unsaturated (but not aromatic) monovalent monocyclic group containing at least one heterocycloatom as described herein, or 2) saturated or partially unsaturated (but not aromatic) monovalent bicyclyl or tricyclic group, wherein at least one ring contains at least one heteroatom as described herein. When the heterocyclyl and heterocycloalkyl group are substituted, they can be substituted on any ring, that is, on any aromatic or non-aromatic ring contained by the heterocyclyl and heterocycloalkyl group. In some examples, such heterocyclyl group includes, but is not limited to, epoxyethanyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1,3-dioxolanyl, dithiolanyl, tetrahydropyranyl, dihydropyranyl, 211-pyranyl, 411-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, benzodioxanyl, benzodioxolyl, benzofuranone, benzopyranone, benzopyranyl, dihydrobenzofuranyl, benzotetrahydrothienyl, benzothiopyranyl, benzoxazinyl, 0-carbolinyl, benzopyranyl, chromonyl, cinnolyl, coumaryl, decahydroquinolinyl, decahydroisoquinolinyl, dihydrobenzisothiazinyl, dihydrobenzisoxazinyl, dihy drofuranyl, dihydroisoindolyl, dihy dropyranyl, dihydropyrazolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dioxolanyl, 1,4-dithiopyranyl, furanonyl, imidazolidinyl, 2,4-dioxo-imidazolidinyl, imidazolinyl, indolinyl, 2-oxo-indolinyl, isobenzotetrahydrofurany 1, isobenzotetrahy drothienyl, isobenzodihydropyranyl, isocoumarinyl, isodihydroindoly1(isoindolinyl), 1-oxo-isodihydroindolyl, 1,3-dioxo-isodihydroindolyl, isothiazolidinyl, isoxazolidinyl, 3 -oxo-isoxazolidinyl, morpholiny 1, 3,5 -dioxo-morpholinyl, octahy droindolyl, octahy droisoindolyl, 1-oxo-octahy droisoindolyl, 1,3-dioxo-hexahydroisoindolyl, oxazolidinonyl, oxazolidinyl, oxiranyl, piperazinyl, 2,6-dioxo-piperazinyl, piperidinyl, 2,6-dioxo-piperidinyl, 4-piperidinone, 2-oxopyrrolidinyl, 2,5-dioxopyrrolidiny 1, quinuclidinyl, tetrahydroisoquinolinyl, 3,5-dioxo-thiomorpholinyl, thiazolidinyl, 2,4-dioxo-thiazolidinyl, tetrahydroquinolinyl, phenothiazinyl, phenoxazinyl, xanthene and 1,3,5-trithiocyclohexyl. Examples of the -CH2- group in the heterocyclyl substituted with -C(0)- include, but are not limited to, 2-oxopyrrolidiny 1, oxo-1,3-thiazolidinyl, 2-piperidone, 3,5-dioxopiperidinyl and pyrimidinedione. Examples of sulfur atom oxidized in the heterocyclyl include, but are not limited to, Date Recue/Date Received 2023-07-07 sulfolanyl and a 1,1-dioxothiomorpholinyl. The heterocyclyl may be optionally substituted with one or more substituents described herein.
In one example, the heterocyclyl is a heterocyclyl composed of 3 to 8 atoms, and refers to a saturated or partially unsaturated monocyclic ring containing 3 to 8 ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur and oxygen atoms. Unless otherwise specified, the heterocyclyl consisting of 3 to 8 atoms may be a carbon group or a nitrogen group, and the -CH2- group may be optionally substituted with -C())-. The sulfur atom of the ring can optionally be oxidized to S-oxide. The nitrogen atom of the ring can optionally be oxidized to an N-oxide. Examples of heterocyclyl consisting of 3 to 8 atoms include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, py razolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahy drothienyl, dihydrothienyl, 1,3-dioxolanyl, dithiolanyl, tetrahydropyranyl, dihydropyranyl, 211-pyranyl, 411-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl , homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl. Examples of -CH2- group in the heterocyclyl substituted with -C(0)- include, but are not limited to, 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-piperidinonyl, 3,5-dioxopiperidinyl and pyrimidinedionyl. Examples of sulfur atom in the heterocyclyl oxidized include, but are not limited to, sulfolanyl and 1,1-dioxothiomorpholinyl. The heterocyclyl consisting of 3 to 8 atoms can be optionally substituted with one or more substituents described herein.
In one example, the heterocyclyl is a heterocyclyl consisting of 3 to 6 atoms, and refers to a saturated or partially unsaturated monocyclic ring containing 3 to 6 ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur and oxygen atoms. Unless otherwise specified, the heterocyclyl consisting of 3 to 6 atoms may be a carbon group or a nitrogen group, and the -CH2- group may be optionally substituted with -C())-. The sulfur atom of the ring can optionally be oxidized to S-oxide. The nitrogen atom of the ring can optionally be oxidized to an N-oxide. The heterocyclyl consisting of 3 to 6 atoms can be optionally substituted with one or more substituents described herein.
In another example, the heterocyclyl is a heterocyclyl consisting of 5 to 6 atoms, and refers to a saturated or partially unsaturated monocyclic ring containing 5 to 6 ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur and oxygen atoms. Unless otherwise specified, the heterocyclyl consisting of to 6 atoms may be a carbon group or a nitrogen group, and the -CH2- group may be optionally substituted with -C(0)-. The sulfur atom of the ring can optionally be oxidized to S-oxide. The nitrogen atom of the Date Recue/Date Received 2023-07-07 ring can optionally be oxidized to an N-oxide. Examples of heterocyclyl consisting of 5 to 6 atoms include, but are not limited to, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1,3-dioxocyclopentyl, dithiocyclopentyl, 2-oxopyrrolidinyl, oxo-1,3 -thiazolidinyl, sulfolanyl, tetrahydropyranyl, dihydropyranyl, 211-pyranyl, 411-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, 2-piperidinonyl, 3,5-dioxopiperidinyl and pyrimidinedionyl, 1,1-dioxylthiomorpholinyl. The heterocyclyl consisting of 5 to 6 atoms may be optionally substituted with one or more substituents described herein.
The term "aryl" used herein, unless otherwise specified, refers to a monovalent C6-Ã14 carbocyclyl system containing at least one aromatic ring, wherein the aromatic ring system is monocyclic, bicyclic, or tricyclic. The aryl group can be connected to the main structure through any of its rings, that is, any aromatic or non-aromatic ring. In some examples, the aryl group is phenyl, naphthyl, bicyclo[4.2.0]octy1-1,3,5-trienyl, indanyl, fluorenyl, or tetrahydronaphthyl. When the aryl group is substituted, it can be substituted on any ring, that is, on any aromatic or non-aromatic ring contained by the aryl group. In some or any examples, aryl is phenyl, naphthyl, tetrahydronaphthyl, fluorenyl, or indanyl. The aryl group is independently optionally substituted with one or more substituents described herein.
The term "heteroaryl" as used herein, unless otherwise specified, refers to a monovalent monocyclic or polycyclic aromatic group, wherein ring atoms comprise at least one heteroatom (in some examples, there being 1, 2, 3, or 4 heteroatoms) independently selected from 0, S(0)0_2 and N
in the ring. The heteroaryl group is connected to the rest of the molecule through any atoms in the ring system in consideration of its valence rules. In some examples, each ring of a heteroaryl group may contains 1 or 2 0 atoms, 1 or 2 S atoms, and/or 1 to 4 N atoms, or a combination thereof, provided that the total number of heteroatoms in each ring is 4 or less, and each ring contains at least 1 carbon atom. In some examples, the heteroaryl group has 5 to 20, 5 to 15, or 5 to 10 ring atoms. When the heteroaryl group is substituted, it can be substituted on any ring.
In certain examples, monocyclic heteroaryl groups include, but are not limited to, furyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl and triazolyl. In certain examples, bicyclic heteroaryl groups include, but are not limited to, benzofuranyl, benzimidazolyl, benzisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl, benzothienyl, benzotriazolyl, benzoxazolyl, furopyridyl, imidazopyridyl, imidazothiazolyl, indazinyl, indolyl, indazolyl, isobenzofuryl, isobenzothienyl, isoindolyl, Date Recue/Date Received 2023-07-07 isoquinolinyl, isothiazolyl, naphthyridinyl, oxazolopyridyl, phthalazinyl, pteridinyl, purinyl, pyridopyridyl, pyrrolepyridyl, quinolinyl, quinoxalinyl, quinazolinyl, thiadiazolopyrimidinyl and thienopyridinyl. In certain examples, tricyclic heteroaryl groups include, but are not limited to, acridinyl, benzindolyl, carbazolyl, dibenzofuranyl, perimidinyl, phenanthrolinyl, phenanthridinyl and phenazinyl.
In some or any examples, the heteroaryl group is phenylene, naphthylene, pyridylidene, pyrimidylidene, pyrazinylidene, pyridazinylidene, thiazolylidene, benzothiazolyl, benzo [d] isothiazolyl, imidazo [1 ,2-a]
pyridyl, quinoly 1, 1H-indolyl, pyrrolo[1,2-b]pyridazinyl, benzofuranyl, benzo[b]thienyl, 1H-indolyl, benzo[d]isoxazolyl, quinazolinyl, 1H-py nolo [3,2-c] pyridyl, pyrazol[ 1,5-a] pyrimidyl, imidazo [1, pyridaziny 1, or pyrazol [ 1,5-a]pyridy 1; each of which is optionally substituted with 1, 2, 3, or 4 groups defined as described herein.
The "solvate" of the present invention refers to the association complex formed by one or more solvent molecules and the compounds of the present invention. The solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol. The term "hydrate" refers to an association complex formed by the solvent molecule, which is water.
When the solvent is water, the term "hydrate" can be used. In some examples, a compound of the present invention can be connected to one water molecule, such as monohydrate; in further examples, a compound of the present invention can be connected to more than one water molecules, such as dihydrate, and in yet another examples, a compound of the present invention can be connected to less than one water molecule, such as hemihydrate. It should be noted that the hydrates of the present invention retain the biologically effectiveness of the compound in its non-hydrated form.
Unless otherwise specified, the compounds used in the examples are available in the market; unless otherwise specified, the methods used in the following examples are common methods.
Example 1 Synthesis of Compound 139 Date Recue/Date Received 2023-07-07 o 2_1..0:203-7,s_,720, ogc ' -Qt._ tur Taif, -la QC- ri.
Compound 13a.-1 Compound 1394 Conlodund 136-.3 >et) 0 .. 1. 06-V...01H:H,,O. FOAG
60 j11 ' IL)."
i,õ,o CI, TEA 12120'sO. I
H2s04. Ac20 f, Et0_,,,i Vc S. NOBH4.1MeOH:H20, 0 C - a E10--I '1:1k- Dalk VO - r.1. HQ -.1 .11eN MOH, EA. -WC
Compound 1119-4 Comnt.,,,, lid 13Y-6 ..
Czimpound 139-6 ph õ
0 N AN õ,Ph 0 0 a: , ,(e. 7 Compound 1)394 *1316480H smceNNO,,04-- -r4' NH,.
H b 107:0'4.µtroim N NUM
SVC
BO¨, bAt Z 111050-rf, FtMeõ, 7PC bet complyand 1i,30-7 Compound 180-0 Compound 1 n-lo , According to the above synthetic route, methyltriphenylphosphonium bromide (163.2 g, 454.6 mmol) was dissolved in anhydrous tetrahydrofuran (1.5 L) under the nitrogen atmosphere protection, and the mixture was cooled to -78 C. Then, n-butyllithium (206.1 mL, 515.2 mmol, 2.5 M) was added dropwise. After addition, the mixture was stirred for 2 hours at 0 C, and then it was further cooled to -78 C. Compound 139-1 (known compound, 78.8 g, 303.1 mmol, dissolved in 100mL of anhydrous tetrahydrofuran) was dripped into the reaction liquid. After addition, the temperature was gradually increased to room temperature, and meanwhile the mixture was stirred overnight. The temperature was then cooled to 0 C, and saturated ammonium chloride solution (500 mL) was gradually added and then the reaction was quenched.
Subsequently, ethyl acetate (300 mL) was added, and the organic phases were successively washed with waster (200 mL *2) and saturated saline, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 20: 1), to obtain 82.0 g of Compound 139-2.
The Compound 139-2 (30.0 g, 117 mmol) was dissolved in anhydrous tetrahydrofuran (300 mL) under the nitrogen atmosphere protection at room temperature. Then, the temperature was cooled to 0 C, and borane dimethyl sulfide (23.4 mL, 234 mmol, 10M) was added. After addition, the mixture was stirred for 20 hours at 0 C. Subsequently, sodium hydroxide solution (28 g, 702 mmol, in 305 mL of water) was added, followed by hydrogen peroxide (80 mL, 30% water solution). The mixture was stirred for 2 hours at room temperature. Subsequently, ethyl acetate (200 mL) was added, and the organic phases were successively washed with water (100 mL *2) and saturated saline, dried over anhydrous sodium sulfate, and concentrated Date Recue/Date Received 2023-07-07 under reduced pressure to obtain 20.5 g of Compound 139-3, which was used for the next reaction without further purification.
The Compound 139-3 (17.0 g, 62 mmol) was dissolved in 100 mL of anhydrous THF
at room temperature, and the iodoethane (14.5 g, 93 mmol) was added. After the temperature was cooled to -10 C, Nail (4.0 g, 99.2 mmol) was gradually added. After addition, the temperature was gradually increased to room temperature, and the mixture was stirred for 5 hours at room temperature.
Then, the temperature was cooled to 0 C, 1 mL of methanol and 150 mL of saturated ammonium chloride solution were added.
Subsequently, ethyl acetate (150 mL) was added, and the organic phases were successively washed with water (100 mL * 2) and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 18.0 g of Compound 139-4, which was used for the next reaction without further purification.
The Compound 139-4(18.0 g, 59.6 mmol) was dissolved in 140 mL of acetic acid at room temperature, followed by 60 mL of water. The mixture was stirred for 1.5 hours at 50 C.
Subsequently, solvent was removed under reduced pressure, and 150 mL of methanol and 50 mL of water were added. Anhydrous sodium bicarbonate was used for adjusting pH to basic. Then, the reaction liquid was cooled to 0 C, and sodium periodate (12.84 g, 60 mmol) was stirred to react for 1 hour at room temperature. Subsequently, 50 mL of methanol was added to the mixture, and filtered. The filtrate was cooled to 0 C, and sodium borohydride (2.66 g, 70 mmol) was added. After addition, the mixture was stirred for 0.5 h at room temperature. The temperature was cooled to 0 C, and acetic acid was used for adjusting pH to neutral. Most of methanol was removed under reduced pressure, and 200 mL of water was then added. The reaction liquid was extracted with dichloromethane (100 mL * 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 11.8 g of Compound 139-5, which was used for the next reaction without further purification.
Benzoyl chloride (4.30 g, 30 mmol) was gradually added to a solution of Compound 139-5 (11.80 g, 35 mmol) and triethylamine (5.30 g, 53 mmol) in dichloromethane (80 mL) under the nitrogen atmosphere protection in an ice bath. After addition, the mixture was stirred overnight at room temperature. Water (100 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (100 mL *3).
Subsequently, the organic phases were combined, concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether! ethyl acetate = 20: 1), to obtain 14.0 g of Compound 139-6.
Date Recue/Date Received 2023-07-07 Concentrated sulfuric acid (0.45 g, 1.5 mmol) was added to a solution of Compound 139-6(14.0 g, 41.6 mmol) and acetic acid (5.00 g, 83.2 mmol) in ethyl acetate (80 mL) at room temperature. After the temperature was increased to 40 C, acetic anhydride (6.36 g, 62.4 mmol), which was diluted with ethyl acetate (10 mL), was dropwise added into the reaction system. After addition, the mixture was stirred for 3 hours at a constant temperature. Then, the temperature was cooled to 0 C, and triethylamine (0.35 g, 3.52 mmol) was added and stirred for 5 min, followed by gradually addition of saturated sodium bicarbonate solution (50 mL). The aqueous phase was extracted with ethyl acetate (50 mL), and the organic phases were combined and successively washed with saturated bicarbonate solution (50 mL) and saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 14.20 g of Compound 139-7.
N,0-bis(trimethylsilyl)acetamide (BSA, 15.23 g, 83.2 mmol) was added to a suspension of Compound 139-8 (known compound, 14.50 g, 37.4 mmol) in 1, 2-dichloroethane (125 mL) under nitrogen atmosphere protection at room temperature, and the mixture was stirred for 2 hours after the temperature was increased to 80 C. The reaction liquid was concentrated under reduced pressure, and methylbenzene (70 mL) was added. The Compound 139-7 (14.20 g, 37.4 mmol) dissolved in methylbenzene (55 mL) was added to the reaction system, followed by addition of trimethylsilyl trifluoromethanesulfonate (TMSOTf, 8.30 g, 37.4 mmol). The temperature was heated to 70 C and the mixture was stirred for 2 hours. Then, the temperature was cooled to room temperature, and water (100 mL) was added into the reaction system. The aqueous phase was extracted with ethyl acetate (200 mL), and the organic phases were combined, washed with water (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane/ ethyl acetate = 1:
10), to obtain 15.0 g of Compound 139-9.
A solution of ammonia in methanol (100 mL) was added to Compound 139-9 (15.0 g, 21.1 mmol) at room temperature, followed by addition of 20 mL of water. The temperature was increased to 50 C, and the mixture was stirred overnight in a closed atmosphere. The reaction liquid was concentrated under reduced pressure, and the residue was heated to reflux with methanol (100 mL) and water (50 mL), stirred vigorously, and purified to obtain 3.60 g of Compound 139-10.
The characteristic data of Compound 139-10 was: MS (m/z) :325.14 [M+1] .1H NMR
(500 MHz, DMSO) 8 10.62 (s, 1H), 8.00(s, 1H), 6.46(s, 211), 5.71 (d, J= 2.1 Hz, 1H), 5.69 (d, J= 5.4 Hz, 1H), 5.02 (t, Date Recue/Date Received 2023-07-07 J = 5.3 Hz, 1H), 4.38 (td, J = 5.4, 2.1 Hz, 1H), 3.98 (dt, J = 8.4, 3.2 Hz, 1H), 3.75 -3.70 (m, 1H), 3.63 (dd, J = 9.4, 6.8 Hz, 1H), 3.55 - 3.50 (m, 1H), 3.48 - 3.40 (m, 3H), 2.56 - 2.52 (m, 1H), 1.11 (t, J = 7.0 Hz, 3H).
o o 0 N NH N l'A'NH
0 II dt, 14..2 POW,/ _in I. ,=1141 r\j_0,...if50; 1 NA-N,H, Ho -'-^=...0,,,N Nifi2 _...P Cb HO 4 -o'-'61/40.AN
Popmeb, VC TA 6 H c PPI12, T'A nr e F. r,t,õ
....
Compound 128-1C1 0 r IrOali = 1 nal 1 CUMIN, md, las-eNIA.Nti MO.OW 0 0 _____________ a.. H04 -0 4 -er''NeyN NAM: u ...E -J n < jit A
1,-0 6H 6H . CI. 6H 6H
TEA k'' 01-1 EL lflEAL e -b., bE, 1 00MpOUrd 13844 CI
H r.
criAte orid biA.444-N H
Mb ORM, r.l. t. Ki & Oaa El d .13Nia 1'6' 3N14,.
COMpOtIld 139.144H, Compound 139 NH2 According to the above synthetic route, the Compound 139-10(1 g, 3.08 mmol) and trimethyl phosphate (10 mL) were added to a reaction flask, and the temperature was cooled to 0 C
under the argon atmosphere protection, then phosphorus oxychloride (0.43 mL, 4.62 mmol) was dropwise added. The mixture was stirred for 4 hours at 0 C. After the reaction was completed, water (4 mL) was added at 0 C, and then the liquid was placed at room temperature and stirred for 0.5 hour. Subsequently, the liquid was washed with dichloromethane (12 mL). The upper aqueous layer was collected, and the organic layer was back- extracted once with water (2 mL). The aqueous layers were combined, concentrated to about 2 mL, then passed through C18 reverse column (gradient elution: acetonitrile: water), and the absorption peak of the desirable compound was collected. Then, the solution passed through ion exchange column (gradient elution:1M TEAB: water) and the peak of the desirable compound was collected. The collected liquid was concentrated under reduced pressure, and freeze-dried to obtain 2.30g of overweight Compound 139-11 (triethylamine salt).
The Compound 139-11(2.3 g, calculated as 3.08 mmol), imidazole (1.9 g, 27.94 mmol). 2,2'-disulfide bipyridine (2.5 g, 11.36 mmol), N,N-dimethylformamide (20 mL), triethylamine (0.76 mL, 5.47 mmol) were added to a reaction flask. Under stirring, triphenyl phosphine (2.9 g, 11.07 mmol) was added. The mixture was stirred for 2 hours and under nitrogen atmosphere protection at room temperature. After the reaction was completed, the reaction system was poured into a mixture solution of sodium iodide (4.4 g, 29.33 mmol) and acetone (50 mL) under stirring, and the mixture was stirred for 10 min at room temperature. Subsequently, it Date Recue/Date Received 2023-07-07 was filtered, and the filter cake was washed with acetone and collected, and dried under reduced pressure at room temperature to obtain 1.2 g of Compound 139-12.
85% phosphoric acid (0.88 g, 7.63 mmol), triethylamine (1.06 mL, 7.63 mmol), N,N-dimethylformamide (12 mL) were added to a reaction flask and stirred for 5 min at room temperature, followed by addition of Compound 139-12 (1.2 g, 2.64 mmol), anhydrous zinc chloride (0.36 g, 2.64 mmol).
The mixture was stirred overnight under the argon atmosphere protection at room temperature. After the reaction was completed, methyl tert-butyl ether (MTBE, 25 mL) was added to the reaction system, stirred, and washed ultrasonically. The supernatant was poured out, and methyl tert-butyl ether (25 mL) was further added to wash bottom pulp again. Subsequently, the supernatant was poured out again, and the pulp was dried under reduced pressure. Water (4 mL) was added to dissolve the pulp.
After dissolution, the solution passed through ion exchange column, and a peak of the desirable product was collected. The collected liquid was concentrated under reduced pressure, and freeze-dried, to obtain 1.23 g of Compound 139-13 (triethylamine salt).
The Compound 139-13 (0.33 g, 0.68 mmol), N,N-dimethylformamide (3 mL) were added to a reaction flask, and iodomethane (0.42 mL, 6.74 mmol) was added under stirring. The mixture was stirred overnight at room temperature. After the reaction was completed, methyl tert-butyl ether (10 mL) was added to the reaction system, stirred and then stand. The supernatant was poured out, and the bottom pulp was dried, followed by addition of water (10 mL) to dissolve the pulp until it became a clean solution. Then, the solution passed through ion exchange column and a peak of the desirable product was collected. The collected liquid was concentrated under reduced pressure and freeze-dried, to obtain 107 mg of Compound 139-14 (trimethylamine salt).
The Compound 139-14 (107 mg, 0.21 mmol), Compound 139-15 (known compound, 162 mg, 0.21 mmol), dimethyl sulfoxide (3 mL) were added to a reaction flask. Zinc chloride (145 mg, 2.1 mmol) was added under the argon atmosphere protection, and the mixture was stirred for 1 day at room temperature.
After the reaction was completed, MTBE was added and stirred. The liquid was stood and then the supernatant was poured out. The precipitate was dissolved in water, passed through ion exchange column, eluted with a gradient elution of 1M aqueous ammonium bicarbonate. An absorption peak of the desirable product was collected, and concentrated under reduced pressure. The residue was repeatably freeze-dried, to obtain 68 mg of Compound 139 (ammonium salt).

Date Recue/Date Received 2023-07-07 The characteristic data of the Compound 139 was: MS (m/z): 1186.25 [M-1]-. 1H
NMR (400 MHz, D20) 8 9.11 (s, 1H), 8.47 (s, 1H), 8.20 (s, 1H), 7.99 (s, 1H), 6.08 (d, J =
5.4 Hz, 1H), 5.85 ¨ 5.82 (m, 2H), 4.99 ¨ 4.95 (m, 1H), 4.68 (d, J = 4.6 Hz, 1H), 4.55 ¨ 4.45 (m, 4H), 4.37 ¨4.23 (m, 7H), 4.13 ¨ 4.10 (m, 1H), 4.03 (s, 3H), 3.74¨ 3.70 (m, 1H), 3.62 ¨ 3.53 (m, 3H), 3.48 (s, 3H), 2.65 ¨2.58 (m, 1H), 1.16 (t, J = 7.0 Hz, 3H); 31P NMR (162 MHz, D20) 8 -0.88 (s, 1H), -11.59 (m, 2P), -22.80 (m, 1P).
Example 2 Synthesis of Compound 3 'XI10,0 I. CHA0C421-120, 229C
1...... Nail, ope. no _'X ,,,i3 2, Num, m poi, , 1,0PiCr"."'NOI....... E2CI. TEA
1,..... ¨ .
2 C - r-t, moc,....,0 -12" I., 3. MON., MOC441120. 0 'C. LI, Me0-1 '134"v% 1)Cud. CPC -nt.
Compound 132-3 Command 3-1 Compound 2-2 A Ph 0 W 0,A,N,Ph rd puuNd szo.......Ø..0Ac 14,1i4HAcCu 139-13 NjilLo Flh BO h()LNIIAt N113/41. H
P001-1, EA. WC moci..../ 'DM -1. Bak hycE ocipc atoc 2. 7140307, PM% TVC
Compound 3-3 c.....poudd 3.4 Compound 3 ', 0 o 0 0. tp(11:1,.... N
0 '( 11 0, wo N4114"h 1:VC'S ' F+D-19-CiehY µe N NH.2 P34SPY' k444 E 16 DL,1 .. ni-it-o,".O-04 N NH2 PO(Ohle)1.1PC TEA 6 J--t PPN, TEA, DIM. Lt. 14'1,, em,, ( t h. k 1311 k''' tdi domu '13n1 Omp Common 34 0 COTIflpound 3-7 Compound 1-13 N XIIILNFI %
n2e0.2 MA MLNIHMLDMIF, 0 vo p_o 0 t I AINHI f Z41%. D'C. r=t= 641 6t1 ........C...r , rl' 6,H aH
TEA
= TEA troip JH
Compound 3-4 Cr rmund A-10 0 Pa4 '4:14¨k ,......1010:40,--0-dN'i"
d 1:09.6.
Otrt ZnCl2, DM, a 7 4 me d -13Nia b. l'i2r4 ,Tnil 314Hd= ..., '''''flify.lrd0 CYlCiek1C1 NCI4s. 1511 Nym tH 1-14112 Nhly Compound 13045 Compound 3 According to the above reaction route, Compound 3-6 was prepared from Compound 139-3 using the procedure for preparation of Compound 139-10, except substituting iodoethane with iodomethane.
The characteristic data of Compound 3-6 was: 111 NMR (500 MHz, DMSO) 8: 10.60 (s, 1H), 7.99 (s, 1H), 6.45 (br, 2H), 5.70(s, 1H), 5.70 ¨ 5.67 (d, J= 6.0 Hz, 1H), 5.03 ¨4.99 (t, J = 5.6 Hz, 1H), 4.41 ¨4.37 (m, 1H), 4.00 ¨ 3.96 (m, 1H), 3.74¨ 3.68 (m, 1H), 3.60 ¨ 3.55 (m, 1H), 3.54¨
3.48 (m, 1H), 3.44¨ 3.39 (m, 1H), 3.26 (s, 3H), 2.58 ¨ 2.52 (m, 1H).
According to the above reaction route, Compounds 3 (ammonium salt) was prepared from Compound 3-6 using the procedure for preparation of Compound 139.

Date Recue/Date Received 2023-07-07 The characteristic data of the Compound 3 was: MS (m/z) :1172.26[M-1]-. III
NMR (500 MHz, D20) 8 9.05 (s, 1H), 8.40 (s, 1H), 8.13 (s, 1H), 7.93 (s, 1H), 6.01 (d, J= 5.5 Hz, 1H), 5.80 (d, J= 5.9 Hz, 1H), 5.78 (s, 1H), 4.93 ¨4.90 (m, 1H), 4.76 ¨4.75 (m, 1H), 4.63 (d, J= 4.9 Hz, 1H), 4.50 (m, 1H), 4.48 (t, J= 4.5 Hz, 1H), 4.43 (m, 1H), 4.41 (t, J= 5.0 Hz, 1H), 4.33 (m, 1H), 4.29 ¨ 4.27 (m, 2H), 4.24 ¨ 4.22 (m, 1H), 4.19 ¨
4.18 (m, 2H), 4.07 ¨ 4.04 (m, 1H), 3.99 (s, 3H), 3.65 ¨3.62 (m, 1H), 3.55 ¨3.52 (m, 1H), 3.43 (s, 3H), 3.32 (s, 3H), 2.61 ¨2.52 (m, 1H); 31P NMR (202 MHz, D20) 8 -0.93 (s, 1H), -11.65 (m, 2P), -22.90 (m, 1P).
Example 3 Synthesis of Compound 135 o 0 >C3-1-6 0 Ni r>(0 ,iir) 1. CH,,CONio izo :;C) fit: 0 ...-ii...._ al lia! MP -PO 2. Na104 Me0H?H2C u -0-a mo o.* laza, TEA
_ft.. ________________________________________________________________ ==
Ho -,_,%4 13\,, 0 ct - rA Bno_/ 4tok 3. MEHL, amouitH20, 0 oic - rt IMO ---,''b -'1Y3K- DM 0 C - r.l.
Compound 139-3 Compound 1151 COMpand 135-2 )11., 111 A NIFI,:N,õ, PI h .<, I ,:i' Compound 139-8 1741,141 Ez0-'*%-Ouro HIS04, ug) I" -0Ac N 1-1Ao 1:11 NP1014e0P1 , H 8.20"-"*".O0 N4A-NIIM
Sno-i 'NA-- MOH, EA, 40 C Bno_si 'Nike 1 BSA ItIcE so 0, ;
2. Mrs 0 rf P Bn0,- .hArc tiMi, ?VC
Compound 135-3 Compound 135-4 Compound 185-5 NX,õ.J JiNyLNI1 #1, PySSPy N''-`19,12 P 13 110-0-0--"NOSI N NH2 1 r)4 4 I õ), - -0 1) fN NH2, POKiLle)b, VC TEA I6H $ . PRIN. TEA, OW, r,t, S 0F1 ,i 1311 0 Bn ban 013n C 0 rnpD Und 135-9 Compound 135-7 compound 135-8 Dec \ II
0 0 0 cj 1 A ' 11 'N111 HolDr% TE A _. Ho .,iy .0 . ild _ 0 N NH. M" I Mir -; ; <" jlt, ,,, 1,, znc4, DO 1* =40' 0- -0- -0'-%=64.11 N-- NH2 +
cl, TEA
811113o TEA ts r = H
bBn compound 135-9 Compound 135-10 0 0 0 n mi ICIlNa re b ,0 e ni, aYkyh". .""."-04-0-191-04-0'N'eti;

HN pi 6 6 6 CtIrt nab DIVISO. r,t Y 1110 - - - d 'bm."1.
o,.., . d H211 O ''' B
3N1-44 d Ha' b HE yH Ho, r141 112 NH2 Compound 1135 Compound 1394 5 According to the above reaction route, Compounds 135-6 was synthesized from Compound 139-3 using the procedure for preparation of Compound 139-10, except substituting iodoethane with bromotoluene.
The characteristic data of Compound 135-6 was: III NMR (500 MHz, DMSO) 8 10.60 (s, 1H), 8.01 (s, 1H), 7.37-7.33 (m, 4H), 7.31-7.26 (m, 1H), 6.45 (s, 2H), 5.71 (d, J= 5.6 Hz, 2H), 5.02 (t, J= 5.4 Hz, 1H), Date Recue/Date Received 2023-07-07 4.51 (q,J= 12.2 Hz, 2H), 4.44-4.40 (m, 1H), 4.06-3.99 (m, 1H), 3.79-3.69 (m, 2H), 3.58-3.51 (m, 2H), 2.66-2.58 (m, 1H).
According to the above reaction route, Compounds 135 (ammonium salt) was synthesized from Compound 135-6 using the procedure for preparation of Compound 139 The characteristic data of the Compound 135 was: MS (m/z) 1248.36[M-1]-. III
NMR (500 MHz, D20)

8 8.34 (s, 1H), 8.06 (s, 1H), 7.92 (s, 1H), 7.26-7.24 (m, 2H), 7.22 ¨ 7.19 (m, 2H), 7.13 (t, J= 7.1 Hz, 1H), 5.98 (d, J= 5.7 Hz, 1H), 5.79 (d, J= 5.8 Hz, 1H), 5.69(s, 1H), 4.93 ¨ 4.90 (m, 1H), 4.74 (d, J= 5.5 Hz, 1H), 4.55 ¨4.52 (m, 1H), 4.50 (s, 1H), 4.47 (t, J = 4.0 Hz, 1H), 4.43 -4.37 (m, 4H), 4.32 (s, 1H), 4.29 ¨4.24 (m, 2H), 4.21 ¨4.18 (m, 3H), 4.04 ¨ 4.01 (m, 1H), 3.99 (s, 3H), 3.77 ¨ 3.74 (m, 1H), 3.63 ¨3.60 (m, 1H), 3.41 (s, 3H), 2.46 ¨ 2.40 (m, 1H); 31P NMR (202 MHz, D20) 8 -0.93 (s, 1H), -11.55 (d, J = 17.4 Hz, 1P), -11.83 (d, J= 19.0 Hz, 1P), -22.85 (t, J= 17.6 Hz, 1P).
Example 4 Synthesis of Compound 141 ...."0 deNto = ..,41 _ meop...,...Ar X ....
12: N.,Y 0 rj .1'el 4011Fil'H'20:54, 0.1C - nt HCr-na4t""0, Boa, TEA
___________________________________________________________________ *
H 30,-..4t '401\-- Nall.THF. 0 r.T. ¨trk- , NAN, a..ir,cm:H201, 5 DO .¨$ 121,.... \ DM, r.t.
kitEri" COMpOPM 1411,2 Compound vori-a CoMpOLInd Id TA 0 ,jP43L 1 k 1 4 Comoro 186-8 NIAN 12'h anD 4,0 H2304. M20 1112Cr:ic er_p_ik '10.3c MOH. EA.10:1Ceorj = 1. WM, 005., ilin 50 'i=:.
2.11615G1 t 11h/de.11:CAeorj"--'' AI' Mo Compound 141,3 COWPIXdOnd 10'4 Compound 141-5 (,,,N fm.i 4.1D(NNI K:eCH
e li 1 Ene**.OAN NA1NH2 ............_1.P Cla HOICIN NAN* PMPA nielann "''').4-5-ce44.610.14, ' PeNH2, (Sti P0(01/1.03, 00 110, = . jo , '.õ_. ,i Pm% 7EPL, .: .IF. A.
?.
macrd0¨: .)1-1 ' hiwAry--1 '131H
Compound '641-6, 0 Corrpa.pi 141-7 0iiropota4 141-5 A
Fupo,, TEA
HO -P -0 -15-47e%Ø.1,1 e'lq1-42 101101,1310F, I i...Y%_,P-4' )511 C5HI IDH ,,., Ti. --6' Mee' Cormpouod 141,9 Mid rodolpound 141,10 C.) 4finft , ,.¨ohl cf ..Jula N y"-- m HO
04 / ZnCl2, 014130 , nt, F n ' d `0No \-- ThMe 041:15 31,11di,.=' He' 'bH y",1 He' Compound 130-10 H7 Compound 141 NH2 Date Recue/Date Received 2023-07-07 According to the above reaction route, Compounds 141-6 was prepared from Compound 139-3 using the procedure for preparation of Compound 139-10, except substituting iodoethane with 2-methoxy- 1-bromoethane.
The characteristic data of Compound 141-6 was: III NMR (500 MHz, DMSO) 8: NMR
(500 MHz, DMSO) 8 10.62 (s, 1H), 8.00(s, 1H), 6.46 (s, 211), 5.71 (d, J= 2.0 Hz, 1H), 5.68 (d, J= 5.4 Hz, 1H), 5.01 (t, J= 5.4 Hz, 1H), 4.38 (td, J= 5.5, 2.1 Hz, 1H), 3.98 (dt, J= 8.5, 3.2 Hz, 1H), 3.75 ¨3.70 (m, 1H), 3.68 (dd, J= 9.6, 6.8 Hz, 1H), 3.57 ¨ 3.42 (m, 6H), 3.24 (s, 3H), 2.58 ¨ 2.52 (m, 1H).
According to the above reaction route, Compounds 141 (ammonium salt) was prepared from Compound 141-6 using the procedure for preparation of Compound 139.
The characteristic data of the Compound 141 was: 1216.02[M-1]-. NMR (500 MHz, D20) 8 9.05 (s, 1H), 8.40(s, 1H), 8.14 (s, 1H), 7.95 (s, 1H), 6.02 (d, J= 5.7 Hz, 1H), 5.83 ¨
5.81 (m, 2H), 4.94 ¨ 4.92 (m, 1H), 4.68 (d, J= 4.9 Hz, 1H), 4.52 ¨ 4.44 (m, 3H), 4.42 (t, J= 4.9 Hz, 1H), 4.34(s, 1H), 4.29 ¨ 4.23 (m, 3H), 4.20 ¨ 4.19 (m, 2H), 4.08 ¨ 4.06 (m, 1H), 4.01 (s, 3H), 3.71 ¨ 3.68(m, 1H), 3.63¨ 3.56(m, 5H), 3.43 (s, 3H), 3.33 (s, 3H), 2.62 ¨2.57 (m, 1H); NMR
(202 MHz, D20) 8 -0.91 (s, 1H), -11.62 (m, 2P), -22.88 (m, 1P).
Example 5 Synthesis of Compound 143 Date Recue/Date Received 2023-07-07 .>' ."0 TN11,11E2er .0 ;.. ClktalZIVIe0 HN,Snu.'*"0"10,L.., 'lb NzE11 TEA
HO-1 43 DOA. Hp. r.t. Hfico .01 .1 3, NalliKt, Atli 14.12c.). Ci c't - Ira, PIFICO--=P 4tr."\. JECK 'O'C - Tr.
DOMInnind 143.2 04:0,0,1,00 las.3 Compound 1+13-1 0 0 IL, Ph E.). NI' crArePh N _ i.,_ KA0 . N Ph 4, I compatmci 1304 N
151.X.NO-0C4 H260.1õ, Ao20 tt1/4(..yr"OA0 A .54.14 0 E, <cdiN 1 A
NRINNON
___________________________________________________________________ Ty'""l'ACr. 14 NNA0 ---,.., 11F2C0¨.? IX AEON, EA, 4,1COC HE100--, rtiAn is B.S.A. OcL. Li.:lin ,. .

1-IF E; D--i bow v wso If, Ph5.10, Tom Denomund 1434 D0M041410 1 .4 Compound 143-5 N ( :kANHI n )1, ' -- NHJ
N:
/ 1 1 0 , ,II tvi ...) 0 ,e hiCr4A60S4 NN112 PC'El:, . IAD-g-Ee""i"- Ni...r1--- 'N. NIHN Py3SPy, Irm.Azole. rnõrnsõ,0 G NI N,t,.-",NH2 GA:c ILA 61 ,7¨F., PP4a, TELõ DMF, !at N''''.' if l ,.' boi bcF2H
OCEIN
Compound 143-6 0 Compound; 113,7 Coropur4 1.. c ; 4 o N %
0 ,0 ,, fr411 1121304, TEA

ii HO-42-0-g-Or. ' N N112 MEIII. Dhlif ZriCi, OW, e.t 61-li (51-1 ---717¨w' 1171;1 Cil I N'ILINH2 .
're A
TEA f '431-1 F.A4 COMnd 143-9 Compound 143-10 ., 0õ..n,nricliNab 44 ,,, 1..N1 peN, 1 1.1EV A, 6 t/NA1 0o, ZnC12, DIASIX Lt. 0,,,, H2N TIFic, tr. i--N
HO' ' O1`44y 14 M He t r!;1H"
ea:mound 139402 CtilltPund 143 Al%
According to the above reaction route, Compound 139-3 (9.0 g, 33mmo1) was dissolved in DCM (80 mL) at room temperature, followed by successively addition of water (80 mL), potassium acetate (12.8 g, 132 mmol), and TMSCF2Br (9.4 g, 46 mmol). After addition, the mixture was stirred for 3 days at room temperature. Dichloromethane (200 mL) was added. Subsequently, the organic phase was successively washed with water (200 mL *2), saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 20 / 1), to obtain 4.4 g of Compound 143-1.
Compound 143-6 was synthesized using the procedure for preparation of Compound 139-10, except substituting Compound 139-4 with Compound 143-1.
The characteristic data of Compound 143-6 was: III NMR (500 MHz, DMSO) 8 10.62 (s, 111), 7.99 (s, 1H), 6.69 (t, JH_F = 70.0 Hz, 1H), 6.46(s, 211), 5.92 (d, J = 5.4 Hz, 1H), 5.73 (d, J= 2.4 Hz, 1H), 5.08 (t, J =
5.4 Hz, 1H), 4.46 (td, J = 5.6, 2.5 Hz, 1H), 4.09 (dd, J = 9.8, 7.0 Hz, 1H), 4.04 ¨ 3.99 (m, 1H), 3.94 (dd, J =

9.8, 6.6 Hz, 1H), 3.74 ¨ 3.69 (m, 1H), 3.58 ¨ 3.50 (m, 1H), 2.71 ¨2.64 (m, 1H).

Date Recue/Date Received 2023-07-07 According to the above reaction route, Compounds 143 (ammonium salt) was synthesized from Compound 143-6 using the procedure for preparation of Compound 139.
The characteristic data of the Compound 143 was: MS (m/z): 1208.06[M-1]. NMR
(500 MHz, D20) 8 9.09 (s, 1H), 8.45 (s, 1H), 8.18 (s, 1H), 7.96 (s, 1H), 6.42 (t, = 75.0 Hz, 1H), 6.04(d, J = 5.4 Hz, 1H), 5.82¨ 5.81 (m, 2H), 4.95 ¨4.92 (m, 1H), 4.72 (d, J = 5.4 Hz, 1H), 4.51 ¨ 4.48 (m, 4H), 4.38 (d, J = 9.5 Hz, 1H), 4.34 ¨ 4.31 (m, 2H), 4.26 ¨4.23 (m, 1H), 4.20 ¨ 4.16 (m, 2H), 4.13 ¨ 4.10 (m, 2H), 4.07 ¨ 4.04 (m, 1H), 4.01 (s, 3H), 3.45 (s, 3H), 2.75 ¨ 2.69 (m, 1H); 31P NMR (202 MHz, D20) 8 -0.92 (s, 1H), -11.61 (m, 2P), -22.89 (t, J = 17.6 Hz, 1P).
Example 6 Synthesis of Compound 137 T,41, .(71:111tu 0 'N
"11 = HJN2 PV5SPY. FmulMall6 r-n4-51-0 01,1 :1, TEA "4 FN. TEA, DN1F, 'N'z'ti 6N8 ."0IH opi e 1-.141 1D$nJHbm compound 054 Ivo OtlIVIOCAMI 1374 0 0 oN Nal 'r4I)ILNI1 H3PO4, 70A ^ DMF - 0 14 I A_ LC12, IMF, Lt. 6H 60 0 -0 '-0 H .6H Nr TEA
bH TEA ''014 017 apci u n d 137-3 Compound 137-4 cr#
0 0 .0 0 hril N
N.r*i 6631 _ N 6 6 6 0.43Htwo N'''v Oto, r.1 I
= r d 'orts d Ncjwsp.õõ,14 i=4"4 31=14.
le .61 yH
14 ' 'b).H
evroaorod 139. 144E12 Catiodunt1 137 N112 According to the above reaction route, Pd/C (5%., 1 g) was added to Compound 135-7 aqueous solution (2.58 mmol) under hydrogen atmosphere and the mixture was stirred overnight.
After the reaction was completed, the reaction liquid was purified by ion exchange column to obtain 1.10 g of Compound 137-1 (triethylamine salt).
An ammonium salt, Compound 137, was synthesized from Compound 137-1 using the procedure for preparation of Compound 139.
The characteristic data of Compound 137 was: MS (m/z): 1158.08[M-1 ]. NMR (500 MHz, D20) 8 9.11 (s, 1H), 8.52 (s, 1H), 8.24 (s, 1H), 7.98 (s, 1H), 6.08 (d, J = 4.6 Hz, 1H), 5.86¨ 5.78 (m, 2H), 4.94 ¨
4.92 (m, 1H), 4.71 (s, 1H), 4.51 ¨4.43 (m, 4H), 4.34 (br, 3H), 4.25 ¨4.15 (m, 4H), 4.00 (s, 3H), 3.87 ¨ 3.83 (m, 1H), 3.77 ¨ 3.75 (m, 1H), 3.47 (s, 3H), 3.22 ¨ 3.17 (m, 2H), 2.61 (br, 1H); NMR (202 MHz, D20) 8 -0.92 (s, 1H), -11.54(m, 2P), -22.81 (m, 1P).

Date Recue/Date Received 2023-07-07 Example 7 Synthesis of Compound 635 >c ,.....jo o 0 31.6.., 1 cF.1,( [Ali imp 50 C
" bl."6"10 MsCI TEA X/Nr... )..10 NaN3 ',> Na104, MeOf 0120. Ck ue a DCM. 00C - rt 0;.: r..0)c- DMFõ ?VC hi3--1 13'..\ 3 w Nai tri c. pc3iwi:0 0 PC . r, r.
Compound 139-3 Coamound 615-1 Cc wound 635-1 0 ,P
0 Nh Al (.1111*t:1 Compozu4134-8 IH 0'4'3/4 OHO
BzCI TEA BrY..."0 ===0 Ha-904 Ao20 13z0ey..0Ac N NHAc jr... _ ,__,.. µ..... ¨ ¨0.
43-1 mti- \ DCM, 0 C = r.t. 1,28.,,j ''''cr1, MOH EA, 40 C
Nr¨, '13Ac 1. BSA, DCE, 80 C
Compoun1635-3 Compound 635-4 Compound 05.5 2, PASCH, P We, 75.0 )11,õ Ph 0 0 0 N' N NH
NIAN ill' <, fy 0 411:1L
N po_9, Ho+06-N N-A-NH2 _ NH3/Me0H HIO"'""O=o WA' Nlii 11ZO 0'''SCy=N N Nripm ¨o-S 1:01 N3---1 ''tyA,n N3 Canpound 635-6 Compound 635-7 Compound 635-3 NXILNH N
0 ci I ,-I-- e j:1-7 Py8SPEirnidm le --rp_o 0 N''' md, IFI3P0,4 TEA
HO .13 0 C1:1 0 -'44"-Csr.Q IN IN''' Niit PPth. TEA, DMF, fit N '''''''' 6bet . . znci,, DMF, Lt.' 6H 6H !¨/.
NlbN TEA
a Compound 635-0 Ounpcmad (IMO

cr cf bme ,,,VI +N
0 0 M. , DeLINEI 0,pr, 1:2.! DMF <.
0 )4 le'NH2 d 'ONa ZnCl2, MOS , r t 1.1. +
611 (1)H
TEA If' .bli 141 µ'' 4 t1,111 I
Compound 635-11 Co:upound 139-15 14"2 0 nj NH-IANIN,"'N''"
H Ho ,4, f 6 6 6 "
-"r c ,....Fi 3N144' d 'N5 y- -T
Compound 635 According to the above reaction route, Compound 139-3 (12.0 g, 47 mmol) was dissolved in anhydrous DCM (120 mL) at room temperature, followed by addition of triethylamine (9.5 g, 93.7 mmol). After the temperature was cooled to 0 C, methylsulfonyl chloride (8.05 g, 70.3 mmol) was gradually added. After addition, the temperature was gradually increased to room temperature, and the mixture was stirred overnight at room temperature. Then, the temperature was cooled to 0 C again, and 150 mL of saturated sodium bicarbonate solution was dropwise added to the mixture. The mixture was separated, wherein the organic Date Recue/Date Received 2023-07-07 phase was successively washed with water (100 mL * 2) and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, to obtain 13.2 g of Compound 635-1, which was directly used for the next reaction without purification.
The Compound 635-1 (15.0 g, 42.6 mmol) was dissolved in 75 mL of DMF at room temperature, followed by addition of sodium azide (11.1 g, 170.5 mmol). The mixture was stirred overnight at 70 C, and then it was cooled to room temperature. Water (500 mL) was added to the reaction liquid, and the liquid was extracted with ethyl acetate (150 mL * 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether! ethyl acetate = 20/ 1), to obtain 9.0 g of Compound 653-2.
Compound 635-7 was prepared using the procedure for preparation of Compound 139-10, except substituting Compound 139-4 with Compound 635-2.
The characteristic data of the Compound 635-7 was: III NMR (500 MHz, DMSO) 8

10.63 (s, 1H), 8.00 (s, 1H), 6.47(s, 2H), 5.96 (d, J= 5.4 Hz, 1H), 5.73 (d, J= 2.2 Hz, 1H), 5.08 (t, J= 5.4 Hz, 1H), 4.44 (td, J=
5.6, 2.3 Hz, 1H), 3.95 (dt, J= 8.3, 3.3 Hz, 1H), 3.74 ¨ 3.67 (m, 1H), 3.64 (dd, J= 12.3, 8.1 Hz, 1H), 3.58 ¨
3.51 (m, 1H), 3.45 (dd, J= 12.3, 5.7 Hz, 1H), 2.63 ¨ 2.56 (m, 1H).
Compound 635 (ammonium salt) was prepared from Compound 635-7 using the procedure for preparation of Compound 139.
The characteristic data of Compound 635 was: MS (m/z): 1183.05[M-1]. NMR (500 MHz, D20) 8 9.09 (s, 1H), 8.50 (s, 1H), 8.23 (s, 1H), 7.97 (s, 1H), 6.08 (d, J= 5.0 Hz, 1H), 5.80¨ 5.79 (m, 2H), 4.95 ¨
4.92 (m, 1H), 4.67 (d, J= 4.8 Hz, 1H), 4.52 (s, 1H), 4.49 ¨4.46 (m, 2H), 4.43 (t, J= 4.7 Hz, 1H), 4.34 ¨4.31 (m, 3H), 4.26 ¨4.23 (m, 1H), 4.21 ¨4.16 (m, 2H), 4.15 ¨4.13 (m, 1H), 4.00 (s, 3H), 3.64¨ 3.60(m, 1H), 3.55 ¨ 3.52 (m, 1H), 3.47(s, 3H), 2.64 ¨ 2.58 (m, 1H); 31P NMR (202 MHz, D20)3 -0.93 (s, 1H), -11.62 (m, 2P), -22.81 (t, J= 18.0 Hz, 1P).
Example 8 Synthesis of Compound 6 Date Recue/Date Received 2023-07-07 0 ?) a Firr441Lri< 41''N 42 Th [ - , 'lath TICIPSCell' ..7". ri.y<721;N k p, h TBDPIKetµe),'N --' - elLiktig ______________________________ lai=
1 ' C.:1 .'1- , , 'ili 6H 4s( , I 0 NYC ( 014 J Nit curipf,.,p,;1 635.7 Compound 54 Compound 134 it MCI, PI, it ,-;, poci Toopsoo"..õ ,- , N - 'N. Vig 3 H ' r E ' \ r r7 lr' ... HICekker .-"r''`IN - = .) 0 4.
DM O'C !t¨i -u4 , ist..1,-. 1_1 Pcrior,ki),õ o'c NH 4 Nf,,, Ciro:!,,,,,,,.; 6-3 co,,,4.,dridia-4 I t) f.õ1..., -L-11- ¨3 ------,-- 4 ---4.14fc helik 12348gFPY. hi '121201*, ri-.6 -0,44y -, N "- 'pi' KA-k, 14 ,P0õ , TEA
la; 1_.,H ¨0!' PP1h. TEA. 01V1P, FL 64=1 6i.42 .1-1.
Zilo2, Dt4F. rib' i bH
,'., NHAic Compound 6.5 Compound 04 .0 1J I, I
N
MK
L
¨. 5 -%1,1:
1%1,W 0 4, IRA If .t)H TEA µ4-1 $ .,,, k ItiAc NW, CE. Irto uttA 5-7 c oipii. , h ,1 84 c.J 4,...,1, .,.......,r1 o ni r 0 0N-17\20".04_04L04-0O'rri -1,---)- y",.

F Hn _ _ , _ cTha , Dmso r.l. 117N A -apil 'P
r=-74 4. 3N/it' OH , hof bli N .N14 I I
Con"mourtd i:i ]!- m. AIN Compound 5 41H2 According to the above reaction route, Compound 635-7 (5.0 g, 15.53 mmol) was dissolved in DMF
(50 mL), followed by addition of imidazole (3.17 g, 46.58 mmol) and TBDPSC1 (5.12 g, 18.63 mmol). The mixture was stirred overnight at room temperature. After the reaction was completed, the reaction liquid was concentrated under reduced pressure to dryness. Ethyl acetate was added for dissolution. The liquid was successively washed with dilute hydrochloric acid, saturated sodium bicarbonate, and saturated saline, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to dryness, and purified by column chromatography to obtain 7.4 g of Compound 6-1.
The Compound 6-1 (5 g, 8.93 mmol) was added to a 250 mL round flask, and THF
(90 mL) was added to dissolve it. Then, 1120 (9 mL) and PPh3 (2.81 g, 10.7 mmol) were added to the mixture. The mixture was heated and reacted overnight at 50 C. LCMS detection showed that the starting materials were converted Date Recue/Date Received 2023-07-07 completely. The solvent was removed by rotary evaporation, and 100 mL of Me0H
was added to stir vigorously. After filtration, 3.99 g of Compound 6-2 was obtained.
The Compound 6-2 (2.0 g, 3.57 mmol) was dissolved in dichloromethane (10 mL) and pyridine (10 mL), and acetylchloride (0.3 mL, 4.28 mmol) was slowly added. The mixture was reacted for 2 hours, and the reaction was quenched by addition of methanol (5 mL). Subsequently, the reaction liquid was concentrated under reduced pressure to dryness, and the residue was purified by column chromatography to obtain 2.1 g of Compound 6-3.
The Compound 6-3 (2.1 g, 3.67 mmol) was added to DCM (20 mL), followed by successively addition of TEA (1 mL, 7.34 mmol) and TEA-3HF (2.36 g, 14.68 mmol). The mixture was stirred for 2 days at room temperature. HPLC detection showed that the starting materials were reacted completely. The solvent was removed by rotary evaporation, and DCM (20 mL) was added and stirred vigorously. After filtration, a white solid product was obtained, and Me0H (20 mL) was further added and the mixture was heated and stirred vigorously. After filtration, a white solid compound was obtained. Finally, 10mL of 1120 (0.1 % TFA) was used for recrystallization, to obtain 250 mg of Compound 6-4.
The characteristic data of the Compound 6-4 was: III NMR (500 MHz, D20) 6 9.07 (s, 1H), 5.99 (s, 1H), 4.64 (d, J= 4.5 Hz, 1H), 4.21 (d, J= 10.6 Hz, 1H), 3.96 (d, J= 13.1 Hz, 1H), 3.69 (dd, J= 13.2, 3.4 Hz, 1H), 3.40 (dd, J= 14.2, 8.7 Hz, 1H), 3.27 (dd, J= 14.1, 5.8 Hz, 1H), 2.56 -2.40 (m, 1H), 1.89 (s, 3H).
According to the above reaction route, Compound 6 (ammonium salt) was prepared from Compound 6-4 using the procedure for preparation of Compound 139.
The characteristic data of the Compound 6 was: MS (m/z): 1199.05[M-1]-. NMR
(500 MHz, D20) 8 9.08 (s, 1H), 8.46 (s, 1H), 8.20 (s, 1H), 7.98 (s, 1H), 6.07 (d, J= 5.3 Hz, 1H), 5.86 (s, 1H), 5.83 (d, J= 5.9 Hz, 1H), 4.97 - 4.94 (m, 1H), 4.76 - 4.75 (m, 1H), 4.63 (d, J= 4.4 Hz, 1H), 4.54 - 4.50 (m, 3H), 4.46 (t, J
= 4.9 Hz, 1H), 4.38 (m, 1H), 4.35 -4.33 (m, 2H), 4.29 -4.26 (m, 1H), 4.24 -4.20 (m, 2H), 4.17 -4.14 (m, 1H), 4.03 (s, 3H), 3.53 (dd, J1= 14.0 Hz, J2 = 8.1 Hz, 1H), 3.47 (s, 3H), 3.29 (m, dd, J1= 14.0 Hz, J2 = 6.1 Hz, 1H), 2.64 - 2.59 (m, 1H), 2.00 (s, 3H); 311) NMR (202 MHz, D20) 8 -0.95 (s, 1H), -11.49 (d, J= 10.9 Hz, 1P), -11.58 (d, J= 12.0 Hz, 1P), -22.82 (t, J= 18.2 Hz, 1P).
Example 9 Synthesis of Compound 5 Date Recue/Date Received 2023-07-07 __,..
PclICA .c.C)-1 ''-).,,__ LIAIH4,THF.0 C
.
EtClOC / 3 'la- \ h4e0H. r.t.- gtooc--. ',._, ,.
-COMPOUnd 130=I CCII1PCIUnti 54 Compound 54 Comp&uhma 1.. '>
,.
1 Ts.H20.0,1190H 1417 r 1 Na104. Mo0N4420, 0 'T.; .. a .'6.)f)-" -7 0, azo"-1/4=O.".::',,, Not Mai THE r ____________________________________ -no , =s. .'"
\''' T '' 3 NABH,,, Mne01-trlizO, 0"C - t.L. hISCHI,C'-..-". .13 '''. _r_ 1,. r' r_ - ca. MPON2C--..' GVIT +AMU 0.4 Couvound 6-5 COrnpatirad 64 i )II, Ph 0 0 N"
N An N
Corr piliind 13g.a 1,LILN 111" Nwi 1-12.304. Ac20 Em0 NroCIL ;mom S/111:N.ANHAc .0 \ - - .,,I
NHYM9C)14 .. l'iteq1/460't TNIAI*12 _______________________________ E.,: ---",.( '),..*N 14 sb/I4Ao Ac01-t. EA, 40 C ms0H2c....,, ',pm I. BSA. DOE, 8We L......., r 2. TIVISOTi. PhMe. 75 'C e' Mai''''' Compound 5-7 60 Cr Compound 54 Compound 54 4,1111.-NH
0 -,.. .--- - f2.= ci .).. F10,8õ..0,-"Ny¨yd,1 = . j -.1,-, fr':,, r , 3 IIII., 41' , riN .41 I:r Pack Am --7,. ,,, LA i Eh L11.0- I ,,t, "W
6/4, , .
.. , P0401,toh, sf0 =- ---- brii '41100' MIK( CeINIONNI 540 Compound 541 0 t. 0 N NH
N F., 0 0 c <1 ) '' 0 0 bc, cl',,,, .11 A., 2'1 1 ' a o-P-o-P-o-"4\-- ----. - '...: N H2 6m 6m --/ 4 TEA ' '1 bi4 TEA
149,_ /.1.0 Compound 5.12 Cempound 5.13 J ¨
p.'"*.µ04/-0.41/...04 "NY' lic \µ,---):02 4 ', 4.= ci bre, o µ
0 , " P. d -ow. DOE, MOO, a 1.µ frkAll 45 't) Fin 3NH4* N
C)õ..r..i0 HO,' i51,1 ry ,),õ),,Wil NO' -km Nyi*I
Qumpound ri ,- NH 1 Compound 3 According to the reaction route, Nail (2.40 g, 60 mmol) was gradually added to tetrahydrofuran solution (100 mL) under the nitrogen atmosphere protection at 0 C. Triethyl phosphonoacetate (12.32 g, 55 mmol) was dropwise added to the reaction system, and the system was stirred for 15 min at 0 C. Then, Compound 139-1(12.9 g, 50 mmol, 40 ml, dissolved in tetrahydrofuran solution) was dropwise added to the reaction system and was stirred for 1 hour. Subsequently, saturated ammonium chloride solution (100 mL) was dropwise added and then the reaction was quenched. After that, ethyl acetate (100 mL) was added, and the organic phase was successively washed with water (100 mL * 2) and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=15/1) to obtain

11.50 g of Compound 5-1.

Date Recue/Date Received 2023-07-07 10% of Pb/C (1.00 g) was added to a solution of Compound 5-1 (10.80 g, 33 mmol) in methanol (100 mL) at room temperature. The mixture was stirred overnight under hydrogen atmosphere. Then, the reaction liquid was filtered by vacuum and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (40 mL). LiA1H4 was dissolved in tetrahydrofuran (50 mL) and after the temperature was decreased to 0 C, the above residue solution was dropwise added. After addition, the temperature was increased to room temperature, and the solution was stirred for 2 hours at room temperature. Subsequently, the reaction liquid was cooled to 0 C and the reaction was quenched after addition of 3mL of ethyl acetate.
Subsequently, 2 mL of water and 10.00 g of anhydrous sodium sulfate were added, and stirred for 5 min.
Siliceous earth was added to filter the solution, and the filtrate was concentrated under reduced pressure, to obtain 8.70 g of Compound 5-3.
Compound 5-9 was prepared from Compound 5-3 using the procedure for preparation of Compound 139-10, except substituting Compound 139-3 with Compound 5-3 and substituting iodoethane with iodomethane.
The characteristic data of Compound 5-9 was: III NMR (500 MHz, DMSO) 8 10.60 (s, 1H), 8.01 (s, 1H), 6.46 (s, 211), 5.73 (s, 1H), 5.61 (d, J= 5.6 Hz, 1H), 5.03 (t, J= 5.3 Hz, 1H), 4.20 (t, J= 5.2 Hz, 1H), 3.90 ¨ 3.85 (m, 1H), 3.77 ¨ 3.71 (m, 1H), 3.58 ¨ 3.50 (m, 1H), 3.42 ¨ 3.35 (m, 2H), 3.21 (s, 3H), 2.34 ¨ 2.27 (m, 1H), 1.82 ¨ 1.69 (m, 1H), 1.59 ¨ 1.50 (m, 1H).
Compound 5 (ammonium salt) was prepared from Compound 5-9 using the procedure for preparation of Compound 139.
The characteristic data of the Compound 5 was: MS (m/z): 1185.95[M-1]-. NMR
(500 MHz, D20) 8 8.35 (s, 1H), 8.05 (s, 1H), 7.94 (s, 1H), 6.00 (d, J= 5.3 Hz, 1H), 5.80 (d, J=
5.2 Hz, 1H), 5.75 (s, 1H), 4.92 (m, 1H), 4.70 (t, J = 5.1 Hz, 1H), 4.49 - 4.47 (m, 4H), 4.41 (m, 1H), 4.33 ¨4.29 (m, 2H), 4.26 ¨4.23 (m, 1H), 4.20 ¨ 4.18 (m, 3H), 4.12 ¨ 4.10 (m, 1H), 3.99 (s, 3H), 3.45 (m, 5H), 3.26 (s, 3H), 2.29¨ 2.23 (m, 1H), 1.77¨ 1.65 (m, 2H); NMR (202 MHz, D20) 8 -0.96 (s, 1H), -11.56 (m, 2P), -22.68 (m, 1P).
Example 10 Synthesis of Compound 153 Date Recue/Date Received 2023-07-07 >C1.1/400 . .>1.s.:...51 1 T-60 Kle0NiNz0õ rt.
" Nali Idel, THF.
135C 2 Pin10õ IVIe0H+1,.0, 0 DC - r.L
. ..., ¨b. .7 5n0H,C--44. NO. 3 Mari. mecailip, 0 C - it 8'14illge¨d` u MK OPC - rt Compound 54 Comppund 1153.1 Compound 153.2 0IN õrPt N
r.4 11, 4 he) i NI cUm und 139-8 ri . , o 1) \ 4)..., 113'D =" HAN. A 2 . 'rz-----%.0". 1/4 Sil 1 N NHAP P B7-0-44Y,ty't6N 111"; NINAP
0. 13....\..- ..,,....,_ BnI)H2C--', AcOHõ EA. 40DC 5.1-101-112C ¨F 1-"Po 1. BE,',i, , Di .1_ iiµd .;; ......
"T=':1, ['NM*, 75 C ancri. vAc Compound 153-3 Compoup,i I '5,.:- 1 Camped , 151-5 N DCLI" NH 4:11j1IH
....4,.., ri'µ
P004, N1431.4. H H 1-: HO "I"'",O...N N N112 ir.
50 C ' H20 , PC(0M03, 0 C Th.,. 1.3f1 ,,,' r.t.
7---' .bH
Bro04-- B;10 Compound 15343 Compound 153-7 I I NH
Q
io ''':Dels:i1441 PyS-SPy., imidazolo -C),.4 0 <:;,11, 41, -'0 ..".....Cy.. N NH
6i-1! .., , P1P113, TEA, IONIF, r t, ' 01, pti ZnC16,, DLIF. r,L
TEA HIcr--` CH Hirre--"I'. 'bH
Compound 1I53.8 Compound 153-9 4 \
IN "'INN N13111`NH
_CI CI
.........1.s.
6H 6H ,...-4 r,L
6H 6H ; .. +
TEA Hor-- tH TEA
Casimir 11 1531O Compound 153-11 in-0 -0-'-''O-44AN112 0 0 0 14 NH
"'-f 04.i<
d'F'It)Ne Znek, , DIASC, LL 1"12N {?' 8 HO''. 15H N y141 No,' bil 1,:i ,õ1.,144 Compound 139-15 NIHI2 Compound 153 NN, Compound 153-6 was prepared from Compound 5-3 using the procedure for preparation of Compound 139-10, except substituting Compound 139-3 with Compound 5-3 and substituting iodoethane with bromotoluene.
The characteristic data of Compound 153-6 was: 11-1 NMR (500 MHz, DMSO) 8 10.61 (s, 111), 8.03 (s, 111), 7.31 ¨7.20 (m, 5H), 6.46 (s, 211), 5.73 (s, 1H), 5.60 (d, J= 5.5 Hz, 1H), 5.06 (t, J= 5.0 Hz, 111), 4.44 (dd, J= 35.4, 12.2 Hz, 211), 4.15 (t, J= 4.8 Hz, 111), 3.89 (d, J= 9.7 Hz, 111), 3.79 ¨ 3.71 (m, 111), 3.61 ¨
3.41 (m, 311), 2.40 ¨ 2.36 (m, 111), 1.86¨ 1.73 (m, 111), 1.61 (dd, J= 12.8, 5.3 Hz, 1H).

Date Recue/Date Received 2023-07-07 According to the reaction route, Compound 153 (ammonium salt) was prepared from Compound 153-6 using the procedure for preparation of Compounds 139 and 137 The characteristic data of the Compound 153 was: MS (m/z): 1172.04[M- l]-. III
NMR (500 MHz, D20) 8 8.96 (s, 1H), 8.39 (s, 1H), 8.12 (s, 1H), 8.00 (s, 1H), 6.01 (d, J= 5.8 Hz, 1H), 5.83 (d, J= 5.6 Hz, 1H), 5.81 (s, 1H), 4.94 ¨ 4.91 (m, 1H), 4.54 (d, J = 4.4 Hz, 1H), 4.50 - 4.46 (m, 3H), 4.41 (t, J = 5.2 Hz, 1H), 4.34 (br, 1H), 4.26 ¨ 4.23 (m, 3H), 4.21 ¨4.19 (m, 2H), 4.15 ¨4.11 (m, 1H), 3.99 (s, 3H), 3.67 ¨ 3.63 (m, 1H), 3.59 ¨3.54 (m, 1H), 3.42 (s, 3H), 2.37¨ 2.32 (m, 1H), 1.78¨ 1.71 (m, 1H), 1.69¨
1.62 (m, 1H); 31P NMR (202 MHz, D20) 8 -0.94 (s, 1H), -11.52 (m, 2P), -22.56 (m, 1P).
Example 11 Synthesis of Compound 4 õ,,,,.... p.... , ,....eõ, , ¨ -\___,.. .),=
--o. ,,õ, , . o.
epoc..........= ===0Ms, - r i. Eh.,.....--' " = ,...c õ..:.õ.= r , Elocc __.., '1 .= MO-f. ,P. , -1 C
Compaund 4- t = . od 42 Compound 5.2 0 A Ph ,-,11c1" 0 0 N' 24 "-Li, 4' I. olt, NH
.r. 1 1.1õ..weaniwund la" "sr( 1,' Li041. THF/H,0 1}' '\.4 E100C¨. '0,1/4 1. BSA. oce., ,00., 4innC
,..-.1 -Compoun .. a TV5:-.7r. Pt,Mo, 750C=
d 44 140 1..oromiund 4.4 Comooeld 4-5 . <,Nliii(1e1 140Ac...HON N#L'Ati2 ''' ''' .... 6,, .= -PO

..__ .,.L I, _ = bii N,õNH
eo= .: EON. 65 V mo).0 .. rlat l'uNm ' ' '... Tr,,..
focamPteld 441 Compound 4-7 Compound 441 t.1711_0, PySSPOmiciazold tj'" -7 -')''...--µ,....t r T Hp':', PP11,3õ TEA, OW. 4: (I)mi,µ.. bt, N sr NH, TEA N1.4. IL
Me-Oungmund 44 CompOUnd 410 ,r, "---ri 1--._?=4 0 0 0- r.iy.tip HO.-11-0.4-0''''''IrL-rN.TØ.e VySSFy Ifokiazolo 6. 6. .:-. ' N NHMPh,, Fl A, OW, ii ,,, ,.' . 'bii NNri TEA tomv?=,..... -NH, N_Hp Compouna 4-11 Campo 11 cl 4 = I.
.N,..
0 0 n 01,--,._ -,..;y 0 ""-0 -4S-- _ d buit,"---o. ,.__,, A 6 6 ., . N -,,..
r cf "T)Nra ZitCla, 011490. a . "Ny- ...,"Th HalU -4 d 'µi HO' 'F'iFi Compound 139-1.4 COirt,41111d I mu .Lil_r, 'i ,,NN
ivi., According to the reaction route, Compound 4-4 was prepared from Compound 5-2 using the procedure for preparation of Compound 139-9, except substituting Compound 139-4 with Compound 5-2.

Date Recue/Date Received 2023-07-07 Compound 4-4 (7.22 g, 10 mmol) was dissolved in tetrahydrofuran (50 mL) at room temperature, followed by adding water (50 mL) and lithium hydroxide (2.52 g, 60 mmol).
After the temperature was increased to 60 C, the mixture was stirred for 20 hours. Subsequently, the temperature was cooled to room temperature, 50 mL of ethyl acetate was added. The aqueous phase was concentrated under reduced pressure to obtain 6 g of Compound 4-5.
The Compound 4-5 (6 g, 10 mmol, saliferous) was dissolved in acetic acid (50 mL) at room temperature.
The temperature was then increased to 60 C, and the mixture was stirred for 20 hours. Subsequently, the temperature was cooled to room temperature, and the liquid was concentrated under reduced pressure to obtain 8 g of Compound 4-6.
The Compound 4-6 (8 g, 10 mmol, saliferous) was dissolved in a solution of dimethylamine in ethanol solution (100 mL) at room temperature. After the temperature was then increased to 65 C, the mixture was stirred for 20 hours. Subsequently, the temperature was cooled to room temperature, and the reaction liquid was concentrated under reduced pressure. The concentrated reaction liquid was firstly passed through C18-column chromatography for desalting, and then separated through medium pressure liquid chromatography, to obtain 0.5 g of Compound 4-7.
The characteristic data of Compound 4-7 was: III NMR (500 MHz, DMSO) 8 10.67 (s, 1H), 8.01 (s, 1H), 6.50 (s, 211), 5.72 (s, 1H), 5.67 (s, 1H), 5.02 (s, 1H), 4.33 (s, 1H), 3.90 (d, J= 9.3 Hz, 1H), 3.74 (d, J=

12.3 Hz, 1H), 3.58 (d, J= 12.2 Hz, 1H), 2.98 (s, 3H), 2.82 (s, 3H), 2.69 ¨2.57 (m, 2H), 2.35 (dd, J= 15.8, 3.4 Hz, 1H).
According to the reaction route, Compound 4 (ammonium salt) was prepared from Compound 4-7 using the procedure for preparation of Compound 139.
The characteristic data of the Compound 4 was: MS (m/z): 1213.09[M-1]. NMR
(500 MHz, D20) 8 9.10 (s, 1H), 8.46 (s, 1H), 8.19 (s, 1H), 7.98 (s, 1H), 6.07 (d, J= 5.5 Hz, 1H), 5.84(d, J= 5.8 Hz, 1H), 5.82 (s, 1H), 4.98 ¨ 4.95 (m, 1H), 4.79 (m, 1H), 4.65 (d, J= 4.1 Hz, 1H), 4.54 ¨
4.51 (m, 3H), 4.46 (t, J= 5.0 Hz, 1H), 4.37 ¨ 4.33 (m, 2H), 4.29 ¨4.26 (m, 2H), 4.23 ¨ 4.20 (m, 2H), 4.14 ¨ 4.12 (m, 1H), 4.03 (s, 3H), 3.47 (s, 3H), 3.06 (s, 3H), 2.89 (s, 3H), 2.74 ¨ 2.61 (m, 2H), 2.57 ¨2.54 (m, 1H);
311) NMR (202 MHz, D20) 8 -0.88 (s, 1H), -11.52 - 11.70 (m, 2P), -22.82 (t, J= 17.9 Hz, 1P).
Example 12 Synthesis of Compound 393 Date Recue/Date Received 2023-07-07 pc '14 jH4-tT"ltrAr"'"NlYkel CISSPY inlidazdia 0 Nra NH2 1-leit N NN2 , N NH ___________ N h11-1 \ PF113, TEA, WAR
r_t, 0bK,70 MeHt4 Out- ti sT Compound 44 Compouad 303-1 Compound 193-2 NPO
011 Ho 4 1-13110.. 1-0 -1-01-0"''&4,2 'CroLeti 1,11,i 44 cy WH ZnC12. t.t. ,y tiMP N , NH
N N69,2 '111A 11).0 T EA.
MN *12 MoHN
Compound 3934 Ovripourid 3133-4 Compound rNH
tr'Lfy Okir,S11 N NH1 045' brde Dr oiCIA4 6 6 6 oso, HN N H 0 g M1J N
d 'OW
HA 0 3N114' +Imo NN
Compound 3,93 Hd Compound 139-15 NH2 191-12, According to the reaction route, Compound 393-1 was prepared using the procedure for preparation of Compound 4-7, except substituting dimethylamine with methylamine and using dimethyl sulfoxide and water as solvents.
The characteristic data of Compound 393-1 was: III NMR (400 MHz, DMSO) 8 10.59 (s, 1H), 8.01 (s, 1H), 7.84(d, J= 4.4 Hz, 1H), 6.46 (s, 2H), 5.74(d, J= 5.4 Hz, 1H), 5.71 (d, J=
1.4 Hz, 1H), 5.02 (t, J= 5.3 Hz, 1H), 4.33 (t, J= 4.6 Hz, 1H), 3.88 (d, J= 9.1 Hz, 1H), 3.75 ¨ 3.65 (m, 1H), 3.55 ¨ 3.48 (m, 1H), 2.67 ¨
2.61 (m, 1H), 2.58 (d, J= 4.5 Hz, 3H), 2.43 (dd, J= 15.2, 8.4 Hz, 1H), 2.19 (dd, J= 15.2, 5.9 Hz, 1H).
According to the reaction route, Compound 393 (ammonium salt) was prepared from Compound 393-1 using the procedure for preparation of Compound 139.
The characteristic data of the Compound 393 was: MS (m/z): 1199.03[M-1]-.41 NMR (500 MHz, D20) 8 9.05 (s, 1H), 8.44 (s, 1H), 8.17 (s, 1H), 7.96 (s, 1H), 6.04 (d, J= 5.5 Hz, 1H), 5.82 ¨ 5.81 (m, 2H), 4.93 (br, 1H), 4.56 (d, J= 4.5 Hz, 1H), 4.51 ¨4.46 (m, 3H), 4.43 (t, J= 5.0 Hz, 1H), 4.34 ¨4.30 (m, 2H), 4.26 ¨ 4.24 (m, 2H), 4.19(s, 2H), 4.10 ¨ 4.08 (m, 1H), 4.01 (s, 3H), 3.43 (s, 3H), 2.66(s, 3H), 2.63 ¨ 2.62 (m, 1H), 2.48 ¨2.41 (m, 2H); NMR (202 MHz, D20) 8 -0.91 (s, 1H), -11.61 (m, 2P), -22.88 (m, 1P).
Example 13 Synthesis of Compound 58 Date Recue/Date Received 2023-07-07 0 0 ,im+1 fNH He'"IeLrirNyhe HO-P-O'''''CrityY
I HO' NANH2 meo..".,A142 i '11.1 i4 NIFI PO% 61-1 1 Ts._ pill NH
Ni H Y
18 Compound 4-5 EtCH. 85 0C

MeCjaN
\P'O NH, eh. in NH
TF A, Compound 584 _if-14IH , Compound 584 0 ir.N ,M41 , irnlidabo10. Na0-P-e*Ify441 ,,,rkirP HO-P-0 -11-06-'441)f)yi CH1,0 11, 4-1-iz'F
PEN, TEA, OW rA. NJ" r.,-t0 41.12 MCI. MAR r.t. TEA. 0 HIN2 r.d.
Mo0--dr "

Compound 58-1, Compound 584 /
0 0 0 P'N.i_ _n. I
Py551Py.
, .:7 NIAIH w .A ..1,..
TEA PPh,, TEA, ME, rt. O un' ii.Ø10,H
NdyNN +
H ¨4Y hail2 WOO
Me0¨/¨

Compound 58.5 compound 58-8 d ohira, 0,/CONA ZnC12., DMSO, r.i.
r---t41 \ H im aC':;,=.Ney0 Congmum4 13845 NHa Compound 58 HI 1511 Hil,õNH
NH, , According to the reaction route, Compound 58-1 was prepared using the procedure for preparation of Compound 4-7, except substituting dimethylamine with 2-methoxyethylamine and using dimethyl sulfoxide as a solvent.
The characteristic data of Compound 58-1 was: III NMR (500 MHz, DMSO) 8 10.62 (s, 1H), 8.00 (s, 1H), 6.45 (s, 211), 5.72 (d, J= 5.3 Hz, 1H), 5.69 (d, J= 1.5 Hz, 1H), 5.02 (t, J= 5.3 Hz, 1H), 4.32 (t, J= 4.4 Hz, 1H), 3.86 (d, J= 9.0 Hz, 1H), 3.73 ¨ 3.65 (m, 1H), 3.53 ¨ 3.48 (m, 1H), 3.33 (t, J= 5.7 Hz, 2H), 3.23 (s, 3H), 3.19 ¨ 3.16 (m, 2H), 2.65 ¨2.57 (m, 1H), 2.43 (dd, J= 15.2, 8.3 Hz, 1H), 2.20 (dd, J= 15.2, 6.0 Hz, 1H).
According to the reaction route, Compound 58 (ammonium salt) was prepared from Compound 58-1 using the procedure for preparation of Compound 139.
The characteristic data of the Compound 58 was: MS (m/z): 1243.03[M-1]-. III
NMR (500 MHz, D20) 8 9.06 (s, 1H), 8.45 (s, 1H), 8.17 (s, 1H), 7.95 (s, 1H), 6.06 (d, J= 5.3 Hz, 1H), 5.80 (d, J= 5.8 Hz, 1H), 5.78 (s, 1H), 4.96 ¨ 4.92 (m, 1H), 4.56 (d, J= 4.4 Hz, 1H), 4.52 ¨ 4.48 (m, 3H), 4.43 (t, J= 4.9 Hz, 1H), 4.34 ¨
4.31 (m, 2H), 4.27 ¨4.25 (m, 2H), 4.20 ¨ 4.17 (m, 2H), 4.12 ¨4.09 (m, 1H), 4.00 (s, 3H), 3.49 (t, J= 5.3 Hz, Date Recue/Date Received 2023-07-07 2H), 3.37 ¨ 3.27 (m, 511), 2.64¨ 2.60 (m, 1H), 2.51 ¨2.43 (m, 211); 31P NMR
(202 MHz, D20) 8 -0.93 (s, 1H), -11.66 (m, 2P), -22.82 (t, J= 18.0 Hz, 1P).
Example 14 Synthesis of Compound 643 a a Ho-P-o HO........eLtili al: kZi. Ne."....e"......A.6 4r. 1:31 f'f,r,Nn POO. 7,-,H ;,: .=¨bil N 1r NH
N HH2 __ ECK 65 C NH., 00KM%. (PC FA NH

NHõ
YiDimirodurd 44 Compound 6434 Compound! 643.2 C, P44 ir"I
Na04_0,---5,11).-f ViSSPy. Irn,Jamle 4 .ntoi ,,,,,,,N64 Hae04-TEA d'PH 6H
.t' coli N H .131 l'' PFt . TE4, DMF, r.; fil AH ZoC6, DMF, Lt . TEA 0 NH.2 r=l= ".. j.....ril=0 x Compound Cinipciund 843.1 _.../
0 0 0 nt ,,.= /
i'll =
"11-1H-e'"..Q.'N.),-; PYSSFV' hmiclamkir.14W-"d2r4j TEA '1:)P1 Y EPN. TEA, IMF, rl. ir'l -:,.. '¨
yi NH, CbmileUnd 643-5 ,rjear" Compurld 543-8 ril3SH2 inq-0-0 NJ 6Na k,_r " .44...
el HI
l91" '04-047-04-43----O- YY ' of bm.
ZnC6, DMSO, r.I. . y pi 0 .. 0 0 .. pht,..
r NS _pi & D '1? H N I, 0 my HI. 'bii Ar114 14 pri--6 IYYlr's?it) Compoundln-15 NI=la Compc,und SO Fide 7.014 N", H
NN.
According to the reaction route, Compound 643-1 was prepared using the procedure for preparation of Compound 4-7, except substituting dimethylamine with hexylamine and using dimethyl sulfoxide as a solvent.
The characteristic data of Compound 643-1 was: III NMR (500 MHz, DMSO) 8 10.60 (s, 1H), 8.00 (s, 1H), 7.88 (s, 1H), 6.44 (s, 2H), 5.73 (d, J = 5.3 Hz, 1H), 5.69 (d, J= 1.7 Hz, 1H), 5.02 (t, J= 5.4 Hz, 1H), 4.31 (t, J= 4.4 Hz, 1H), 3.89 ¨ 3.85 (m, 1H), 3.72 ¨ 3.67 (m, 1H), 3.55 ¨ 3.46 (m, 1H), 3.11 ¨2.93 (m, 2H), 2.65 ¨ 2.58 (m, 1H), 2.41 (dd, J = 15.2, 8.3 Hz, 1H), 2.18 (dd, J = 15.2, 8.3 Hz, 1H), 1.40 ¨ 1.35 (m, 2H), 1.27 ¨ 1.20 (m, 6H), 0.85 (t, J= 6.8 Hz, 3H).
According to the reaction route, Compound 643 (ammonium salt) was prepared from Compound 643-1 using the procedure for preparation of Compound 139.
The characteristic data of the Compound 643 was: MS (m/z): 1269.08[M-1]-. III
NMR (500 MHz, D20) 8 9.17 (s, 1H), 8.61 (s, 1H), 8.33 (s, 1H), 8.07 (s, 1H), 6.13 (s, 1H), 5.81 (m, 2H), 4.95 (br, 1H), 4.57 ¨ 4.44 (m, 5H), 4.35 (m, 2H), 4.27(m, 2H), 4.20 ¨ 4.16 (m, 3H), 4.02(s, 3H), 3.47(s, 3H), 3.08(m, 2H), 2.67(s, Date Recue/Date Received 2023-07-07 111), 2.47 (m, 21I), 1.38 (m, 21I), 1.13 (m, 61I), 0.75 (m, 311); 31P NMR (202 MHz, 1)20) 8 -0.90 (s, 111), -11.61 (m, 2P), -22.74 (m, IP).
Example 15 Synthesis of Compound 633 N N

CO ,,i HOty--.*.N ,,,?'===e N
ypt.,,t0 c, not N _ ,, NH .
110"=.O. N NH2 ) T TBSC, unidazoto N''' 'brio .-1,NI.II LIAIH4 Et0H. 80 C NH2 / )....0 NH, THE, Cr'C
J b DMF. M. 0 Ng' C.) Compound 4-6 Compound 633-1 Compound 633-2 P=N 0 P1 Ho 40j_0.......O.N7),,,e Tescre..O.N yiy0 1.40''.....ty'N yi''-r (SH
z."bo N _.y.NH
; =
c 'OTEIgi 'yNH 3HFITEA.. TEA :I 'f:),H N,...y,NH POCia .
f_Ni j=-=-N 41.12 P0(0Moh, Cet TEA

NH2 THF. 400C
j¨N
¨1 ,D..) %DJ
Compound 633-3 Compound 633-4 Compound 633-5 0 0 F:N 0 0 ,,,...,.e ,,,,,,0 f=6N
Nao 4 _0,.......,c7..N , .stõ,i0 HO 4-04-0 N 0 PySSPy, imOdzole 614 ' N= , Hip04..TEA 61.1 OH ---'1 N.yNH CH31 . µc j S boi 'OH ME
PPn3,, TEAõ DMF. r,I, N 4042 ZnCg2, IMF, a TEA
1,...1,1 NH2 r.t.
0 ¨1 Compound 633-6 Compound 633-7 /
0 0 p--.N<

HO.
PAW,. iraldazois Na0 4-0 -0 -o6) -'14 ).0 OH OH i7 ,tifi N ,...y, NH I. = A., ..
TEA
1,?' NH2 *
0 PP43. WA. II fil u" µ'.). blet N NH2 (--.. N
Compound 633-8 .) Compound 633-9 n44-0 N Nr),,, y NH2 N4,-2, 6_ 0 0 0 r, &I
yl.....( Na d' broomz-% 0,4r94". 0 N NH2 . , 1 6 6 6 ¨
d -131,4a ZoC12 l. . ouso. r. 1., ====P'14 i HO = 0 b N'''-'N
.r".4 H2N 3NH4. Otp, 1 HO'' 'bH N,yNH Compound139=15 ,-NH2 Compound 633 Ha' '-etH N
...),,,,NH

According to the reaction route, Compound 633-1 was prepared from Compound 4-6 using the procedure for preparation of Compound 4-7, except substituting dimethy lam me with morpholine.
TBSC1 (2.50 g, 18.97 mmol) was added to the solution of Compound 633-1 (1.87 g, 4.74 mmol), imidazole (1.61 g, 23.70 mmol) in anhydrous N,N-dimethylformamide (20.0 mL), and the mixture was stirred overnight. The reaction liquid was poured into ice water (100 mL), stirred for 10 min, and filtered by vacuum.
The filter cake was washed with water (20 mL * 2), and then collected. After the filter cake was purified by Date Recue/Date Received 2023-07-07 column chromatography on silica gel (ethyl acetate / methanol = 10/1), 1.88 g of Compound 633-2 was obtained.
Lithium aluminum hydride (0.21 g, 5.55 mmol) was added in batches to a suspension of Compound 633-2 (1.728 g, 2.77 mmol) in anhydrous tetrahydrofuran (55.0 mL) under the nitrogen atmosphere protection at 0 C. After addition, the mixture was stirred overnight. Water (2.0 mL) was dropwise added to the reaction system in an ice bath and stirred for 10 min, followed by addition of anhydrous sodium sulfate (4.0 g). Then, the mixture was stirred for 10 min, filtered by vacuum. The filter cake was washed with tetrahydrofuran (20 mL * 3), and the filtrate was collected to concentrate under reduced pressure.
The residue was purified by column chromatography on silica gel (dichloromethane /methano1=8/1) to obtain 1.52 g of Compound 633-3.
Triethylamine (2.1 mL, 14.76 mmol) and triethylamine trihydrofluoride (2.4 mL, 14.76 mmol) were successively added to a solution of Compound 633-3 (1.50 g, 2.46 mmol) in tetrahydrofuran (15.0 mL) at room temperature. After the temperature was increased to 40 C, the mixture was stirred overnight.
Subsequently, the reaction liquid was concentrated under reduced pressure to obtain residue, which were purified by C18 column chromatography (acetonitrile / water), to obtain 0.64 g of Compound 633-4.
The characteristic data of Compound 633-4 was: III NMR (500 MHz, DMSO) 8 10.58 (s, 111), 8.00 (s, 111), 6.44 (s, 211), 5.79 (s, 111), 5.74 (s, 111), 5.07-4.95 (m, 111), 4.24 (d, J= 4.7 Hz, 111), 3.90-3.85 (m, 111), 3.74 (d, J= 12.0 Hz, 1H), 3.60-3.50(m, 5H), 2.49-2.33 (m, 5H), 2.35-2.27 (m, 2H), 1.75-1.66 (m, 1H), 1.56-1.47 (m, 1H).
According to the reaction route, Compound 633 (ammonium salt) was prepared from Compound 633-4 using the procedure for preparation of Compound 139.
The characteristic data of the Compound 633 was: MS (m/z): 1241.06[M- 1]-. 1H-NMR (500 MHz, D20) 8: 8.42 (s, 1H), 8.16 (s, 1H), 7.97 (s, 1H), 6.06 (d, J = 6.0 Hz, 1H), 5.91 (s, 1H), 5.85 (d, J = 5.7 Hz, 1H), 4.94 (s, 1H), 4.87 (t, J= 5.5 Hz, 1H), 4.66 (d, J= 4.4 Hz, 1H), 4.54(t, J= 4.3 Hz, 2H), 4.50 ¨4.46 (m, 2H), 4.37 (s, 1H), 4.32 ¨ 4.30 (m, 2H), 4.26 ¨ 4.22 (s, 4H), 4.04(s, 3H), 3.92 (br, 3H), 3.41 (s, 3H), 3.35 ¨ 3.18 (m, 5H), 2.58 ¨ 2.52 (m, 1H), 2.09 ¨ 2.00 (m, 1H), 1.99 - 1.92 (m, 1H), 1.31 (t, J= 7.2 Hz, 2H). 31P-NMR
(202 MHz, D20) 8: -0.85 (s,1P), -11.36 (mõ2P), -22.74 (m,1P).
Example 16 Synthesis of Compound 309 Date Recue/Date Received 2023-07-07 N
t I DetZ. y.,Le;km%
T00P80^..b.,, N 14)42 aza. PT 00P80'"NO,.N N 'F70I:At NO"NO=0 D T
OM, (PC
siel:t3m tioz.bH tiez H
Conmound Cormommd 303,1 Compound 103,2 7,:)1c4 o FOCl2 HD D PySSFY, imIdozole. *4_0 N NH2 KNOM014, 0 C TEA H PPhs, TEA. DMF, r.t epin tNtiBz Compound 309-3 Compound 3051-4 0 0 <IAIM 0 0 1-13K4, TEA
ZnC6, DMF, "Dtt '..1/45. N W 1.4611 41-C4T0.--."60*N
6,1 eim TEA ( .1111 TEA bN
NHB, NNW:
Com mund 333-5 Compound 300.6 0-1148:14)1.1, X4:1?' _ , N
04, DMe 'kr 11.r oõpe d st*" ZnC1 DM 2, SD, it, 3mm,- d Y¨/-1t7IP
14cr 1511 Ny"" Pirt 1)11 Y4F1 Compound 139.15 Wio Compound 30d NH2 According to the reaction route, Compound 309-2 was prepared from Compound 6-2 using the procedure for preparation of Compound 6-4, except substituting acetyl chloride with benzoyl chloride.
The characteristic data of Compound 309-2 was: III NMR (400 MHz, DMSO) 8 10.55 (s, 1H), 8.49 (t, J= 5.2 Hz, 1H), 8.04 (s, 1H), 7.84 (d, J= 7.2 Hz, 2H), 7.54 (t, J= 7.3 Hz, 1H), 7.48 (t, J= 7.4 Hz, 2H), 6.47 (s, 2H), 5.78 (d, J= 3.7 Hz, 2H), 5.13 (t, J= 5.1 Hz, 1H), 4.41 (t, J= 4.3 Hz, 1H), 4.06-4.00(m, 1H), 3.81-3.73 (m, 1H), 3.65-3.55 (m, 2H), 3.42-3.37 (m, 1H), 2.72-2.62 (m, 1H).
According to the reaction route, Compound 309 (ammonium salt) was prepared from Compound 309-2 using the procedure for preparation of Compound 139.
The characteristic data of the Compound 309 was: MS (m/z): 1261.05[M-1]. NMR
(500 MHz, D20) 8 9.06 (s, 1H), 8.33 (s, 1H), 8.04 (s, 1H), 7.91 (s, 1H), 7.60 (d, J= 7.6 Hz, 2H), 7.33 (t, J= 7.4 Hz, 1H), 7.25 (t, J= 7.6 Hz, 2H), 5.96 (d, J= 5.6 Hz, 1H), 5.91 (s, 1H), 5.76(d, J= 5.6 Hz, 1H), 4.90 ¨ 4.86 (m, 1H), 4.68 (d, J= 4.2 Hz, 1H), 4.51 ¨4.47 (m, 3H), 4.39 ¨4.35 (m, 2H), 4.31 (s, 1H), 4.23 ¨4.18 (m, 5H), 3.99 (s, 3H), 3.80 ¨ 3.75 (m, 1H), 3.44 ¨ 3.41 (m, 1H), 3.35 (s, 3H), 2.82 ¨2.76 (m, 1H);
31P NMR (202 MHz, D20) 8 -0.91 (s, 1H), -11.42 (m, 2P), -22.71 (m, 1P).
Example 17 Synthesis of Compound 311 Date Recue/Date Received 2023-07-07 TN0F30.'"1/45.N 14H2 MCI. PI' TN0F50-"'"4-6..N N NHp. ThFn-F-A, 1-51 OCM, 060 THF, OW, rt L:ISH c4141M":1511 Cornpuund 6-2 Carnpotind 311-1 06664 311-2 1,,61 PCICI1 l" 0 PySSPy, imIdazole *41_0 N Nmi2 PO(IN14), 00C TEA aH Plo1N, OMF, r.1. 6N.
twi t314 311-1M3 NW&
C6m66Nr41 311-3 Compound 311-4 0, 0 _________________ HO
+14 'Ll'"`LNH
0 0 IjkNH
"
HANN Mak IF
ZnCl. DMF, ri. 614 TEA '1:131 TEA

Componud 311-S Conpound 311-6 I*146174 .112 C32-911¨

c1/411 bmeth," ri HO 6- 4 ei d EnCl. DIM, 113 0 4'15 :CYti-1:1()"r 3N144*

\LYNH
Cranpo11139-15 tiltd Compound ail Nit I
According to the reaction route, Compound 311-2 was prepared from Compound 6-2 using the procedure for preparation of Compound 6-4, except substituting acetyl chloride with methylsulfonyl chloride.
The characteristic data of Compound 311-2 was: III NMR (500 MHz, DMSO) 6 10.61 (s, 1H), 7.96 (s, 1H), 6.87 (t, J= 5.6 Hz, 1H), 6.45 (s, 2H), 5.75 (d, J= 5.4 Hz, 1H), 5.71 (d, J= 2.0 Hz, 1H), 5.07 (t, J= 5.3 Hz, 1H), 4.46 ¨ 4.44 (m, 1H), 3.97¨ 3.94(m, 1H), 3.73 ¨ 3.69 (m, 1H), 3.57¨
3.52 (m, 1H), 3.28 ¨ 3.22 (m, 1H), 3.06 ¨ 3.01 (m, 1H), 2.92 (s, 3H), 2.54 ¨ 2.50 (m, 1H).
According to the reaction route, Compound 311 (ammonium salt) was prepared from Compound 311-2 using the procedure for preparation of Compound 139.
The characteristic data of the Compound 311 was: MS (m/z): 1235.05 [M-1]-. NMR
(500 MHz, D20) 8 9.06 (s, 1H), 8.36 (s, 1H), 8.14 (s, 1H), 7.99 (s, 1H), 6.04 (d, J= 5.6 Hz, 1H), 5.83 (s, 1H), 5.76 (d, J= 5.6 Hz, 1H), 4.90 ¨ 4.86 (m, 1H), 4.68 (d, J = 4.3 Hz, 1H), 4.50 ¨ 4.45 (m, 3H), 4.39 ¨4.35 (m, 2H), 4.31 (s, 1H), 4.23 ¨4.15 (m, 5H), 3.99 (s, 3H), 3.69¨ 3.65 (m, 1H), 3.37¨ 3.33 (m, 4H), 3.35 (s, 3H), 2.90 (s, 3H), 2.52 ¨ 2.49 (m, 1H); 31P NMR (202 MHz, D20) 8 -0.91 (s, 1H), -11.48 (m, 2P), -22.92 (m, 1P).
Example 18 Synthesis of Compound 299 Date Recue/Date Received 2023-07-07 i:111.1210,r' )111,11.1 T ?144NN
1190P60".O-^ N NN3 He 11 1130P50""NO-J4 N, NH2 31-FT11FA. EA , OCM, 0 C , , 11-1F, e.

0=, Orul Doropdind 6-2 Fi Compound 2.,g5-1 o H Compound 299-2 POCIt H0-W-0,1&19 I Nil Ft, FAWN imidozole " N NH2 P00291M2, 0 C TEA CSH PFIti, TEA, OMR r.t. &hi a %/111Corninnind 299-3 014 Co ,npound 299-4 µ 0 21. =i`11:41^1 0 0 0 0 A.
1131;04, TEA _11_,,i1_,,,,,.....ol: ri,..-..NH2 Mol, CHF_ ,4_04_0.......)16,,ni NH2 ZnC12, DMF, M. HO'c-51.7qiii' Lk i LA . ,),^mj.,' TED. ("4 194 TEA bH
0i411 Compound 2995 0 'CCompound 309-5 0 i&I NA_ *13;:").#11N112 ' === ' '----o-11¨o¨Lo¨il¨o"-O-49--r' 041 bm."4.., 6 6 o = N
d -'3Na ZnClt, DM30. r.t. Hn H
41-'0 '15 H0 3NH4" '4C14H
"CP' 't31-1 wy"H
Compound 13945 41/42 Compound 29P NH, According to the above reaction route, formic acid (127 L, 3.37 mmol) and EDCI
(0.81 g, 4.21 mmol) were successively added to a solution of Compound 6-2 (1.50 g, 2.81 mmol), HOBT (0.46 g, 3.37 mmol), and triethylamine (0.78 mL, 5.61 mmol) in anhydrous N,N-dimethylformamide (42 mL) under the nitrogen atmosphere protection at room temperature, and the mixture was stirred overnight. Then, the reaction liquid was poured into ice water (160 mL), stirred for 10 min, and filtered by vacuum. The filter cake was washed with water (20 mL), collected, and purified by column chromatography on silica gel (dichloromethane/methanol =8/1) to obtain 0.86 g of Compound 299-1.
Triethylamine trihydrofluoride (0.5 mL, 3.06 mmol) and triethylamine (0.4 mL, 3.06 mmol) were successively added to a solution of Compound 299-1(0.86 g, 1.53 mmol) in anhydrous tetrahydrofuran (20 mL) at room temperature. After the temperature was increased to 40 C, the mixture was stirred overnight.
The reaction liquid was then concentrated under reduced pressure to obtain residue, which were vigorously stirred with acetonitrile (20 mL) to obtain 0.39 g of Compound 299-2.
The characteristic data of Compound 299-2 was: 111 NMR (500 MHz, DMSO) 8 9.46 (s, HD, 8.11-8.04 (m, 111), 8.02 (s, HD, 8.00 (s, 111), 6.49 (s, 211), 5.77-5.70 (m, 211), 5.12-5.05 (m, 111), 4.38-4.33 (m, 111), 3.96-3.90 (m, 111), 3.75-3.69 (m, 111), 3.58-3.50 (m, 111), 3.32-3.30 (m, 111), 3.24-3.17 (m, 111), 2.50-2.44 (m, 111).
According to the reaction route, Compound 299 (ammonium salt) was prepared from Compound 299-2 using the procedure for preparation of Compound 139.

Date Recue/Date Received 2023-07-07 The characteristic data of the Compound 299 was: MS (m/z): 1185.4 [M-1]-. 111 NMR (500 MHz, D20) 8 8.39 (s, 1H), 8.13 (s, 1H), 8.06 (s, 1H), 8.03 (s, 1H), 6.01 (d, J = 5.6 Hz, 1H), 5.85 - 5.83 (m, 2H), 4.92 -4.89 (m, 1H), 4.73 -4.71 (m, 1H), 4.59 (d, J = 3.9 Hz, 1H), 4.50 -4.44 (m, 3H), 4.40 -4.38 (m, 1H), 4.36 -4.33 (m, 2H), 4.24 - 4.14 (m, 5H), 3.99 (s, 3H), 3.59 -3.55 (m, 1H), 3.42 (s, 3H), 3.35 - 3.31 (m, 1H), 2.61 -2.55 (m, 1H); 31P NMR (202 MHz, D20) 8 -1.03 (s, 1H), -11.29 (m, 2P), -22.04 (m, 1P).
Example 19 Synthesis of Compound 219 1.110 HO Ao0 0 AtO i=N
L-)..Priel'IP., ftW)MAP Lt 4 ( ,,,,j40, NO t...,04.11,eyo-..."."10.1102 Tamem ie OAc N -T pPha, DIM Mar 1-3. ( bms MHz bms 141.4 OMo M11H2 Compound 34 Compound 219-1 Compound 219.2 Ac0 ifl HO Mi 19u0NO,TEA.31.1F LerNYY....."'CL010,2 1) H2N ONIS0,90r o 2)14-1.3,44e0H li_..? 'tlfl N Y*1 'btie F UM t MI
Compound 219-3 Compound 219-4 N x11,141.1 1 P003 1.402d-0 1 N'A'N'AN FY4SPY. '' 1 'zglit r0,44_0,.....).1 WA', w i POtOroM03, OPC 78A OH , =15H PPtia, TEA FIL.F, Ft 6P1B ,11.--/
H
'6.11a K bH
otou Comm.-RI PIM Compuumd 291-6 11 (ILLNH
zri t`N1,1 1 mka oweye ,I, .
ci. _______ DmF, r,t 6H 61 r.1. 61-1 61-H H
TEA i:';1614:15F1 TA
bms Compound 219.7 Compound 2194 \

rNi-10'".."'OJNI12 ClrY:1"A".-0-1?-0-0-0-1-+OIYIN"2 ONa il %taie hi ex,. II .,,,,,N 0 6 0 = , N
ov, znclb Dm, r't' r HI!. M 0 CI*11 d 'ONo ,T, e 31411,e cir '6 HI' bH NI'S" id bH N,,irripi CQmpoland 13045 " CaMpOLAnd 219 NH
According to the above reaction route, acetic anhydride (3.3 mL, 35.33 mmol) was dripped into a suspension of Compound 3-6 (5.00 g, 16.06 mmol), DMAP (0.20 g, 1.61 mmol), and triethylamine (18 mL, 128.48 mmol) in anhydrous acetonitrile (65 mL) in an ice bath under the nitrogen atmosphere protection.
After addition, the temperature was naturally increased to room temperature and the mixture was stirred overnight. Then the reaction liquid was concentrated under reduced pressure to obtain residue, which were vigorously stirred with methanol (50 mL) to obtain 5.50 g of Compound 219-1.
P-nitrobenzene ethanol (3.42 g, 20.49 mmol) and triphenylphosphine (7.16 g, 27.32 mmol) were successively added to a suspension of Compound 219 (5.40 g, 13.66 mmol) in methylbenzene (140 mL) under the nitrogen atmosphere protection at room temperature, and the mixture was stirred for 30 min. Then, Date Recue/Date Received 2023-07-07 DLAD (5.4 mL, 27.32 mmol) was gradually dripped into the reaction system.
After addition, the mixture was stirred for 22 hours. The reaction liquid was then concentrated under reduced pressure to obtain residue, which were purified by column chromatography on silica gel (ethyl acetate) to obtain 4.00 g of Compound 219-2.
Triethylamine trihydrofluoride salt (36 mL) was added to a solution of Compound 219-2 (3.90 g, 7.16 mmol) in anhydrous tetrahydrofuran (30mL) under the nitrogen atmosphere protection in an ice bath, and the mixture was stirred for 5 min. Then, tert-butyl nitrite (2.1 mL, 17.90 mmol) was gradually dripped into the reaction system. After addition, the mixture was stirred for 2 hours under a constant temperature. Saturated sodium bicarbonate aqueous solution was dropwise added to the system for regulating pH to neutralization.
Subsequently, water (100 mL) was added, and the liquid was extracted with ethyl acetate (40 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain residue, which were purified by column chromatography on silica gel (petroleum ether/ethyl acetate =1/3) to obtain 2.25 g of Compound 219-3.
Isopropylamine (1.7 mL, 19.55 mmol) was added to a solution of Compound 219-3 (2.14 g, 3.91 mmol) in anhydrous dimethyl sulfoxide (15 mL) at room temperature. The temperature was increased to 65 C in a sealed atmosphere, and the mixture was stirred overnight. After the temperature was cooled to room temperature, a solution of ammonia in methanol (30 mL) was added, and the mixture was reacted for 5 hours at room temperature in a sealed atmosphere. The reaction liquid was concentrated under reduced pressure to obtain residue, which was purified by column chromatography on silica gel (dichloromethane/methanol =7/1) to obtain 1.26 g of Compound 219-4.
The characteristic data of Compound 219-4 was: 111 NMR (500 MHz, DMSO) 8 10.22 (s, 1H), 7.94 (s, 1H), 6.25 (d, J = 7.4 Hz, 1H), 5.72 (d, J = 2.0 Hz, 1H), 5.68 (d, J = 5.2 Hz, 1H), 4.90 (t, J = 5.5 Hz, 1H), 4.53-4.49 (m, 1H), 4.05-3.95 (m, 2H), 3.73-3.67 (m, 1H), 3.63-3.58 (m, 1H), 3.53-3.47 (m, 1H), 3.44-3.40 (m, 1H), 3.27 (s, 3H), 2.65-2.59 (m, 1H), 1.18 (d, J= 2.6 Hz, 3H), 1.17 (d, J=
2.6 Hz, 3H).
According to the reaction route, Compound 219 (ammonium salt) was prepared from Compound 219-4 using the procedure for preparation of Compound 139.
The characteristic data of the Compound 219 was: MS (m/z): 1214.05[M-1]-. 111 NMR (500 MHz, D20) 8 9.12 (s, 1H), 8.55 (s, 1H), 8.29 (s, 1H), 8.04 (s, 1H), 6.06 (d, J= 5.1 Hz, 1H), 5.89 (s, 1H), 5.80 (d, J= 5.7 Hz, 1H), 4.95 ¨4.92 (m, 1H), 4.84 ¨ 4.83 (m, 1H), 4.52 (s, 1H), 4.49 ¨ 4.44 (m, 3H), 4.37 ¨ 4.34 (m, 3H), 4.26 ¨ 4.16 (m, 3H), 4.11 ¨4.09 (m, 1H), 4.06 ¨ 4.05 (m, 1H), 4.03 (s, 3H), 3.71 ¨3.68 (m, 1H), 3.61 ¨3.58 Date Recue/Date Received 2023-07-07 (m, 1H), 3.45(s, 3H), 3.34(s, 3H), 2.66 ¨ 2.60 (m, 1H), 1.25 (d, J= 6.6 Hz, 3H), 1.20 (d, J= 6.5 Hz, 3H);
31P NMR (202 MHz, D20) 8 -0.95 (s, 1H), -11.60 (m, 2P), -22.72 (m, 1P).
Example 20 Synthesis of Compound 110 % a *Ny, NI:_y,'=.-OtrN )i),INH 2 aYt21'''''''''0-11LOSL0j-Or'''01.11 Irli'jr d "Dita -211-911¨== H,li kl' 004 %Me 6H µ 6+1 DMSO, ri. 31,614. 0 TEA bil 47rj.442111g \*",!Cyhr7,r ii HS -bvi 45. b11-1 ftampound 3-10 0001p00r01 110,1 131111parr11 110 According to the reaction route, Compound 110 (ammonium salt) was prepared from Compound 3-10 using the procedure for preparation of Compound 139, except substituting Compound 139-15 with Compound 110-1.
The characteristic data of the Compound 110 was: MS (m/z): 1133.07[M-1]. 111 NMR (500 MHz, D20) 8 9.07 (s, 1H), 8.50 (s, 1H), 8.23 (s, 1H), 7.86 (d, J= 8.1 Hz, 1H), 6.10 (d, J= 5.9 Hz, 1H), 5.91 (d, J= 4.8 Hz, 1H), 5.80- 5.78 (m, 2H), 4.97 ¨ 4.90 (m, 1H), 4.65 (d, J= 4.9 Hz, 1H), 4.57(s, 1H), 4.49 ¨ 4.45 (m, 2H), 4.35 ¨ 4.22 (m, 7H), 4.16 ¨ 4.14 (m, 1H), 4.09 ¨ 4.06 (m, 1H), 4.02 (s, 3H), 3.67 ¨ 3.64 (m, 1H), 3.57 ¨ 3.54 (m, 1H), 3.49 (s, 3H), 3.34 (s, 3H), 2.62 ¨ 2.57 (m, 1H); 31P NMR (202 MHz, D20) 8 -1.07 (s, 1H), -11.65 (m, 2P), -22.92 (m, 1P).
Example 21 Synthesis of Compound 197 . k, hritix N z,,./ duni ti 1 0 4"
, , 14 H
, NH
04-0.47-1 . 2 'Oft &Cie H7Nr roe 17'6 61-1 C k 4 1iDMSa ri.
TEA ( bH alHe '''''Fr.-µi4fID
HO
H01 to, '1IN' bH YEE4 gound 3-10 Cerirreoune 101 Nu, According to the reaction route, Compound 197 (ammonium salt) was prepared from Compound 3-10 using the procedure for preparation of Compound 139, except substituting Compound 139-15 with Compound 197-1.
The characteristic data of the Compound 197 was: MS (m/z): 1186.06[M-1]-. 111 NMR (500 MHz, D20) 8 8.99 (s, 1H), 8.33 (s, 1H), 8.11 (s, 1H), 7.92 (s, 1H), 6.01 (d, J= 5.4 Hz, 1H), 5.80 (d, J= 5.8 Hz, 1H), 5.79 (s, 1H), 4.94 ¨ 4.91 (m, 1H), 4.75 ¨ 4.71 (m, 1H), 4.64 (d, J = 4.9 Hz, 1H), 4.51 (m, 1H), 4.48 ¨ 4.45 (m, 1H), 4.41 (t, J= 5.0 Hz, 1H), 4.34 ¨ 4.23 (m, 4H), 4.20 ¨ 4.17 (m, 2H), 4.08 ¨
4.05 (m, 1H), 3.98 (s, 3H), Date Recue/Date Received 2023-07-07 3.66¨ 3.63 (m, 111), 3.56 ¨ 3.53 (m, 111), 3.46 (s, 311), 3.33 (s, 311), 3.08 (s, 311), 2.60 ¨2.54 (m, 111); 31P
NMR (202 MHz, D20) 8 -0.92 (s, 111), -11.65 (m, 2P), -22.90 (m, 1P).
Example 22 Synthesis of Compound 195 o i'M
o .41 rnq -11CrNH,-ca''.."y--LI'' ' 0--5-c-5-0-14 I eINK, 7S1Nn ZhClz ,Iiiihi Me 6 0.kri (Si i Oili , . . µ hir d HO -''' DINO rl ' t5'1121)'71(9 si-rm I
iiHR 1.,10-1 bli N4yHH
Ooripcond 1,10 cw.itour. I VA ii Commix: 116 NIt.
¶
According to the reaction route, Compound 195 (ammonium salt) was prepared from Compound 3-10 using the procedure for preparation of Compound 139, except substituting Compound 139-15 with Compound 195-1.
The characteristic data of the Compound 195 was: MS (m/z): 1171.04[M- 1 ]. 111 NMR (500 MHz, D20) 8 9.15 (s, 111), 8.52 (s, 111), 8.25 (s, 111), 7.94 (s, 111), 6.14 (s, 111), 5.72 (s, 111), 5.64 (d, J = 5.3 Hz, 111), 4.63 ¨4.61 (m, 211), 4.54 - 4.49 (m, 211), 4.39 (t, J= 4.8 Hz, 1H), 4.34 ¨
4.30 (m, 311), 4.19 ¨ 4.17 (m, 111), 4.14 ¨ 4.11 (m, 211), 4.05 ¨ 4.00 (m, 5H), 3.91¨ 3.86(m, 111), 3.70¨ 3.67 (m, 411), 3.61 ¨3.58 (m, 111), 3.34 (s, 311), 2.67 ¨2.61 (m, 111); 31P NMR (202 MHz, D20) 8 6.53 (s, 111), -11.52 (m, 2P), -22.61 (m, 1P).
Example 23 Synthesis of Compound 171 HO r- 1 ¨0-6 4-ci ar,LIFI 4 N
mo c4 air:15,111H, -iP-u -0-6 N JH Niii Mel. DM, oLpi -c: i-0 N Num e 161..i =1=.t- PC14010102. Ose 6h 611 ..'4%.c..):'.

bme NI-7 TEA. 'llme b H OH OH
TEA f t)H
OW
Compound Ifi Cornpokuld 171.1 Compound 171-2 0.1 1bma HN ,,,,,o4 H 1,10 0i 0 d bme N*tõ
ZTICIn VMSO, r,t. 014 1., HA 4,16 4, d '10Na mad, 3N)H4' jHe' .151,1 N YN1H illd 6 N yNIH
Compound 139-16 1'1* Compound 171 46.
According to the above synthetic route, Compound 3-6 (1 g, 3.2 mmol) was added into a two-neck flask, and trimethyl phosphate (15 mL) was added to the flask. Subsequently, the temperature was cooled to 0 C, and methylene bis(phosphonic dichloride) (1.61 g, 6.43 mmol) was added under the argon atmosphere protection. After addition, the mixture was reacted for 3 hours. HPLC showed that the reaction was completed and the reaction was stopped. Sodium bicarbonate aqueous solution (269 mg in 2m1 water) was added. After Date Recue/Date Received 2023-07-07 addition, the mixture was reacted at room temperature for 5 min. The reaction liquid was concentrated under reduced pressure to remove water, followed by addition of methyl tertiary butyl ether (2 * 30 mL). The liquid was sonicated for 2 min, and then the supernatant was removed. The residue was separated through C18 column, purified by ion exchange column, and freeze-dried to obtain 1.9 g of Compound 171-1 (triethylamine salt).
Compound 171(ammonium salt) was prepared using the procedure for preparation of Compound 139, except substituting Compound 139-13 with Compound 171-1.
The characteristic data of the Compound 171 was: LC-MS[M-H]-: 1170.11. 1H-NMR
(500 MHz, D20) 8: 9.35 (s, 1H), 8.51 (s, 1H), 8.22 (s, 1H), 7.96 (s, 1H), 6.09 (d, J= 4.8 Hz, 1H), 5.82 (s, 1H), 5.78 (d, J= 5.6 Hz, 1H), 4.93 ¨4.89 (m, 1H), 4.76 ¨4.72 (m, 1H), 4.67 (d, J= 5.0 Hz, 1H), 4.50 ¨ 4.48 (m, 2H), 4.41 ¨4.39 (m, 2H), 4.37 ¨4.35 (m, 1H), 4.33 (m, 2H), 4.23 ¨ 4.20 (m, 3H), 4.10 - 4.07 (m, 1H), 3.99(s, 3H), 3.71 ¨
3.67 (m, 1H), 3.62 - 3.58 (m, 1H), 3.46 (s, 3H), 3.35 (s, 3H), 2.72 ¨2.67 (m, 1H), 2.56 ¨ 2.38 (m, 2H).31P-NMR (202 MHz, D20) 8: 16.88 (d, J= 8.2 Hz,1P), 7.65 (dd, J= 25.2, 7.9 Hz,1P), -0.90 (s,1P), -11.28 (d, J
= 25.9 Hz,1P).
Example 24 Synthesis of Compound 173 c 0 ct_trz4_,,, orsi"
N 6 6 tr11-111"
64 &I bhib LIC31-9,?rt" d bmip Pywy.into 160.110, 4"m hiljl-diA PFIN. I =TEA =
ccd Ace boo 14.1.A4 44ea, wThe N yNki 14-41)41 173.1" gampama Campoted 1734 XIX
HO N NI== compourd wow IF-A ZotCtbiDivISOõ t Compowt etrixamd 17344 Hrfr !
0 6 6 ti F.40 - = d b." '4' 0,ve stott -0 "C
Commie] 171 According to the above synthetic route, Compound 173-1(0.5 g, 0.533 mmol) was added into a two-neck flask, and trimethyl phosphate (5 mL) was added to the flask.
Subsequently, the temperature was cooled to 0 C and methylene bis(phosphonic dichloride) (266 mg, 1.066 mmol) was added under the argon Date Recue/Date Received 2023-07-07 atmosphere protection. After addition, the mixture was reacted for 3 hours.
Subsequently, methylene bis(phosphonic dichloride) (266 mg, 1.066 mmol) was added further and the mixture was reacted overnight at 0 C. LCMS showed that the reaction was completed and the reaction was stopped. The sodium bicarbonate aqueous solution (269 mg in 2m1 water) was added. After addition, the mixture was reacted at room temperature for 5 min. The reaction liquid was concentrated under reduced pressure to remove water, followed by addition of methyl tertiary butyl ether (2 * 30 mL). The liquid was sonicated for 2 min, and then the supernatant was removed. The residue was separated and purified by C18 column, and freeze-dried to obtain 1.0 g of crude product.
The above crude product (1.0 g) was dissolved in ammonium hydroxide (15 mL) and the mixture was reacted for 4.5 hours after it was heated to 50 C. Subsequently, the heating was stopped, and the mixture was reacted overnight at room temperature. LCMS showed that the reaction was completed and the reaction was stopped. The reaction liquid was concentrated and dried, followed by addition of water (100 mL) for diluting the liquid. The liquid was purified by ion column (1120: TEAB), and freeze-dried to obtain 354 mg of Compound 173-2 (triethylamine salt).
The Compound 173-2 (triethylamine salt, 354 mg, 0.298 mmol) was dissolved in DMF (3mL), and then imidazole (101 mg, 1.49 mmol) and 2,2 '-dithiobipyridine (131 mg, 0.596 mmol) were added, followed by addition of triethylamine (30 mg, 0.298 mmol) and triphenylphosphine (156 mg.
0.596 mmol) under three argon gas displacement, and the mixture was reacted for 6 hours at room temperature. HPLC showed that the reaction was completed and the reaction was stopped. A solution of sodium iodide (223 mg, 1.49 mmol) in acetone (35 mL) was poured into the reaction liquid, and the mixture was stirred for 5 min, and centrifuged.
The supernatant was removed to obtain a solid, and acetone (2 * 20 mL) were added to it. The mixture was centrifuged twice, and the solid was concentrated under reduced pressure and dried to obtain 243 mg of Compound 173-3.
Compound 3-7 (230 mg, 0.58 mmol) was dissolved in N,N-dimethylformamide (5 mL), and iodomethane (0.42 mL, 6.74 mmol) was added under stirring. The mixture was stirred overnight at room temperature. After the reaction was completed, MTBE (10 mL) was added to the reaction system and stirred.
Then, the reaction liquid was stand, and the supernatant was poured out. The bottom pulp was dried and 10 mL of water was used to dissolve it well. After that, the solution passed through ion exchange column and a peak of the desirable product was collected. The collected solution was concentrated under reduced pressure, and freeze-dried to obtain 210 mg of Compound 173-4 (triethylamine salt).

Date Recue/Date Received 2023-07-07 Compound 173-4 (87 mg, 0.215 mmol) was added into a single-neck flask, followed by addition of DMSO (5.4 mL), Compound 173-3 (243 mg, 0.284 mmol), and zinc chloride (387 mg, 1.79 mmol), and the mixture was reacted overnight at room temperature. HPLC showed that the reaction was completed and the reaction was stopped. Water (100 mL) and ethylene diamine tetraacetic acid disodium (930 mg) were added and stirred until the solution was clear. The solution was purified by ion column (1120: ammonium bicarbonate), then freeze-dried to constant weight, and finally 48.6 mg of Compound 173 (ammonium salt) was obtained.
The characteristic data of the Compound 173 was: LC-MS[M-H]-: 1170.11. 1H-NMR
(500 MHz, D20) 8: 9.23 (s, 1H), 8.61 (s, 1H), 8.26 (s, 1H), 8.02 (s, 1H), 6.09 (d, J = 4.8 Hz, 1H), 5.81 -5.80 (m, 2H), 4.94 -4.91 (m, 1H), 4.66 (d, J = 4.6 Hz, 1H), 4.51 -4.47 (m, 3H), 4.43 (t, J = 4.6 Hz, 1H), 4.39 (d, J = 10.2 Hz, 1H), 4.34 (m, 1H), 4.30 -4.27 (m, 1H), 4.23 -4.17 (m, 3H), 4.12- 4.10(m, 1H), 3.99 (s, 3H), 3.73 - 3.69 (m, 1H), 3.63 - 3.59 (m, 1H), 3.48 (s, 3H), 3.35 (s, 3H), 2.70 - 2.65 (m, 1H), 2.47 (t, J = 20.4 Hz, 2H).31P-NMR (202 MHz, D20) 8: 16.79 (s, 1P), 7.80 (dd, J = 25.4, 6.8 Hz,1P), -0.89 (s, 1P), -11.31 (d, J= 26.5 Hz, 1P).
Example 25 Synthesis of Compound 189 o 0 IcLyN11 rni4L0,õ,õtrprjh",õdõ,,(N112 NI kt;il ema .; , 0=

'ONa btlip 113PC4, *OH
)71,kst: ZnC12, RAF,. T.t.
N P
bfri N ,yNH HO wyN11 N112 iN H2 Compound ij.i Compound \ 0 1<ti4jOiti 0 -IL; -0 4-0 ---N=14 -1,4 H2 PyrESPy, imidemole N NH2 Compound 1 M)-1 OH OH .
TEA $111 PPPI3, TEA, IMF, rt. 0 Offn tme:bH ZoC12, OMSO, Compound 3.10 comoMMO 1B9-2 01.51:41?¨ 0 "".
Me 4H Cr6 N4*
N, NH
Compound 189 412, Date Recue/Date Received 2023-07-07 According to the above synthetic route, 85% phosphoric acid (89 mg, 0.77 mmol) and N,N-dimethylformamide (2.5 mL) were added to a reaction flask, and triethylamine (108 !IL, 0.77 mmol) was added under stirring. After the mixture was stirred for 5 min at room temperature, Compound 139-15 (200 mg, 0.26 mmol) was added. The mixture was reaction overnight. After the reaction was completed, MTBE
(6 mL) was added to the reaction system. Then, the reaction liquid was sonicated and the product was precipitated completely. After the supernatant was poured out, the solid precipitation was dissolved in water (6 mL) until the solution was clear. Subsequently, the solution passed through ion exchange column (gradient elution: 1M TEAB/water) and a peak of the desirable product was collected. The collected solution was concentrated under reduced pressure, and freeze-dried to obtain 150 mg of Compound 189-1 (triethylamine salt).
The Compound 3-10 (triethylamine salt, 200 mg, 0.261 mmol), imidazole (88.5 mg, 1.3 mmol), 2,2'-dithiodipyridine (115 mg. 0.52 mmol), N,N-dimethylformamide (2 mL), triethylamine (40 !IL, 0.26 mmol) were added to a reaction flask, and triphenylphosphine (137 mg, 0.52 mmol) was added under stirring. The mixture was stirred for 5 hours under the nitrogen atmosphere protection and at room temperature. After the reaction was completed, the reaction system was poured into a mixture solution of sodium perchlorate (160 mg, 1.3 mmol) and acetone (5 mL), and the mixture was stirred for 10 min at room temperature. Then, the mixture was filtered, and the filter cake was washed with acetone. After that, the filter cake was collected, dried under reduced pressure at room temperature, to obtain 168 mg of Compound 189-2.
The Compound 189-1 (triethylamine salt, 140 mg, 0.125 mmol), Compound 189-2 (102 mg, 0.15 mmol), and dimethyl sulfoxide (2 mL) were added to a reaction flask, followed by addition of zinc chloride (255 mg, 1.87 mmol) under the argon atmosphere protection, and the mixture was stirred for 80 hours at room temperature. After the reaction was completed, the reaction system was added into a solution of EDTA-2Na (630 mg, 1.87 mmol) in water (6 mL), and water was further added for diluting the reaction liquid to about 15 mL, and then the solution passed through ion exchange column. The liquid was eluted with 1M ammonium bicarbonate aqueous solution to collect a peak of the desirable product, which was concentrated under reduced pressure. The residue was freeze-dried repeatedly to obtain 22 mg of Compound 189 (ammonium salt).
The characteristic data of the Compound 189 was: LC-MS[M-H]: 1251.87. 1H-NMR
(500 MHz, D20) 8: 9.14 (s, 1H), 8.53 (s, 1H), 8.21 (s, 1H), 7.89 (s, 1H), 6.05 (d, J = 4.4 Hz, 1H), 5.72 (d, J = 5.1 Hz, 1H), 5.69 (s, 1H), 4.90 -4.87 (m, 1H), 4.74 (t, J = 5.0 Hz, 1H), 4.60 (d, J = 4.6 Hz, 1H), 4.48 (br, 2H), 4.44 (t, J

Date Recue/Date Received 2023-07-07 = 4.6, 111), 4.37 ¨ 4.30 (m, 411), 4.24 ¨ 4.08 (m, 411), 3.97 (s, 311), 3.68 ¨
3.64 (m, 111), 3.58 ¨ 3.54 (m, 111), 3.44 (s, 311), 3.31 (s, 311), 2.63 ¨2.57 (m, 1H).31P-NMR (202 MHz, D20) 8: -0.99 (s,1P), -11.65 (m, 2P), -22.91 (m,2P).
Example 26 Synthesis of Compound 191 HO f=t4 H)L-rPN y)'-e pork, mph*
NH OH 6H 6H , _____ H 614 6H
N
H O tH 1:12 hio T41,42 HOI-C -P-OH
Othe 2 OH 6H oroo armor i CanranUnd 191,1 (--= = r1r11 191,2 Fmtl N 4'1 6Na, 4 N C'4:y-4,7"
00" 6tVie 4*" 21412, r 0M$0, N HO
1"14.' 'ONs = H2 d HCI OH 1'4 wy" t>...14 y0 NI V, Hp' 614 NJ ay Ni CouvouirTd 139.15 Dienpotad 1%1 1`4142 According to the above synthetic route, Compound 3-6 (200 mg, 0.64 mmol) and trimethyl phosphate (4 mL) were added to a reaction flask. The temperature of the reaction system was decreased to about 0 C
under argon displacement protection, phosphorus oxychloride (0.1 mL) was added to the system and the mixture was stirred for 3 hours at 0 C. Phosphorus oxychloride (0.1 mL) was further added and the mixture was continued to react for 3 hours under stirring at 0 C. Subsequently, the temperature of the system was decreased to about -10 C, and a mixture solution of methylene diphosphonic acid (450 mg, 2.56 mmol), acetonitrile (2 mL), and tripropylamine (1.3 mL) was added, followed by further addition of tripropylamine (0.85 mL), and the mixture was stirred for 3.5 hours at -10 C. The reaction system was placed in an ice bath and the reaction was quenched with TEAB (20 mL). After that, the mixture was stirred overnight at room temperature. The reaction system was concentrated under reduced pressure to dryness. MTBE (15 mL) was added to the residue, which were washed ultrasonically. Subsequently, the supernatant was poured out and the bottom pulp was dissolved in water (6 mL). Saturated sodium bicarbonate was used for adjusting pH to 7 to 8. The liquid was concentrated to dryness under reduced pressure and then was dissolved in water (4 mL) until the liquid was clear. Further, the liquid passed through C18 reverse column (gradient eluent: acetonitrile/
water) and a peak of desirable product was collected. Finally, the collected liquid was concentrated to 12 mL
of solution under reduced pressure, and then passed through ion exchange column (gradient eluent: 1M
TEAB/water) to collect a peak of desirable product, which was concentrated under reduced pressure, and freeze-dried to obtain 113 mg of Compound 191-1 (triethylamine salt).

Date Recue/Date Received 2023-07-07 The Compound 191-1 (triethylamine salt, 105 mg, 0.11 mmol), N,N-dimethylformamide (1.5 mL), and iodomethane (55 !LL, 0.88 mmol) were added to a reaction flask, and the mixture was stirred for 8 hours under the sealed condition at room temperature. After the reaction was completed, excess iodomethane was removed by vacuum under reduced pressure. Water (6 mL) was added for dissolving the system.
Subsequently, the liquid was purified by ion column chromatography (gradient eluent: 1M TEAB/water) to collect a peak of the desirable product, which was concentrated under reduced pressure, and freeze-dried to obtain 69 mg of Compound 191-2 (triethylamine salt).
The Compound 191-2 (triethylamine salt, 65 mg, 0.075 mmol), Compound 139-15 (59 mg, 0.075 mmol), and dimethyl sulfoxide (1.5 mL) were added to a reaction flask, followed by addition of zinc chloride (102 mg, 0.75 mmol) under the argon atmosphere protection, and the mixture was stirred overnight at room temperature. After the reaction was completed, the reaction system was added to a solution of EDTA-2Na (252 mg, 0.75 mmol) in water (6 mL). The reaction liquid passed through ion exchange column, and eluted with 1M ammonium bicarbonate solution to collect a peak of the desirable product, which was concentrated under reduced pressure, and freeze-dried repeatedly to obtain 49 mg of Compound 191 (ammonium salt).
The characteristic data of the Compound 191 was: LC-MS[M-H]: 1250.15. 1H-NMR
(500 MHz, D20) 8: 9.31 (s, 1H), 8.68 (s, 1H), 8.30 (s, 1H), 7.95 (s, 1H), 6.13 (d, J= 4.3 Hz, 1H), 5.77 (d, J= 5.2 Hz, 1H), 5.68 (s, 1H), 4.91 -4.87 (m, 1H), 4.70 (t, J= 5.2 Hz, 1H), 4.56 (d, J= 4.7 Hz, 1H), 4.52 -4.49 (m, 2H), 4.47 (t, J= 4.9 Hz, 1H), 4.39 -4.27 (m, 2H), 4.33 (br, 2H), 4.28 -4.22 (m, 2H), 4.19 - 4.12 (m, 2H), 3.97(s, 3H), 3.70 (dd, J= 10.1, 7.6 Hz, 1H), 3.60 (dd, J= 10.1, 5.8 Hz, 1H), 3.52 (s, 3H), 3.35 (s, 3H), 2.67 -2.59 (m, 3H). 31P-NMR (202 MHz, D20) 8: 7.98 (d, J= 25.5 Hz, 2P), -0.99 (s,1P), -11.28 (m, 2P).
Example 27 Synthesis of Compound 33 Date Recue/Date Received 2023-07-07 1_ ci-liaooKei-i,o. so oc o ,.
"i91.... NoH, Ci.E;1.1 C i , ,er. Ho ,-''',..0 13201. TEA
.0 2. Wul0i.. 1,0 Hito, 0 9C - LI. 1__?, b'....................
He; J '1Y\ 7H1,, IJ ''cz, - r.t.
0 i .',0)jc- 3. WAN, M.OHM20, 0 90 = LI. _ p-....e. .- \ CCM. 00C - Lt.
Compound 150-3 rf Compound 33-1 49"-- Compound 00-2 0 0, 1 Ph N . .1.z.
ci. ..,,I, CAMPDUAd i3CW! ..j. -1-1 - N
0 B/0Ow0Ac.....
H220,. Acip N NHAe = :15,-.r=I ¨ --'N '"- n NI-In 1 N141111a H .
____________________ I. H _,..
1.2,--47 i:,=,,C= 50 9C
2. T M12 WY. Phil, ire riP'''' bAD
Compound 334 Compound 334 Compound 33-5.
0 o o 0 !4 jet-N9 cif 1,, 11.01.0-,..,peN' MANI,' PySSPy. imidszoldo r,,,, j_07,...õ0, Ho-"sc, ,riN N NH2 ¨,..Paela He.
NH:2 PCIOMinh, CPC TEA
OH e b.
Compound' 33-5 0 Compound 33-7 'Compound 03-13 D
%
1-121A04, TEA Zn H r 24 . 4....Li_i.u,,,_ci _..**(hi Hok.,NH .1.. alp ?, c2 iele, JIDMF.
rd..' ei: ' lii.r 2 """"""""""10 0 -.I' - ri 4 = .. tA Hit +
r.l.
TEA t bH 60 doi . .
TEA i3 '01-I
Conspound S:14 Compound 33.10 r=f4 CIN'''. I '' . 4L0.4L04:0 0 0 0 ...........p.....04,NH2 HP1? 6 6 6 d boa H T - -"..ume4,14 gilt Znqb DONA ni Nri 0* .0his Z
331 d 0 PO A H4t \`*=IC),N;,,,,4,,e0 l'N'tt.r.:', 1L,_.
....0 Compound 130-15 HH2 Compounri 33 N K2 õ
According to the reaction route, Compound 33-6 was prepared from Compound 139-3 using the procedure for preparation of Compound 139-10, except substituting iodoethane with bromopropylene.
The characteristic data of Compound 33-6 was: 41 NMR (500 MHz, DMSO) 8 10.62 (s, 1H), 8.00 (s, 1H), 6.46 (s, 211), 6.07 ¨6.03 (m, 1H), 5.71 (d, J = 2.1 Hz, 1H), 5.69 (d, J =
5.4 Hz, 1H), 5.45 ¨ 5.43 (m, 1H), 5.33 ¨5.30 (m, 1H), 5.02 (t, J = 5.3 Hz, 1H), 4.38 (td, J = 5.4, 2.1 Hz, 1H), 3.98 (dt, J = 8.4, 3.2 Hz, 1H), 3.75 ¨ 3.70 (m, 1H), 3.63 (dd, J = 9.4, 6.8 Hz, 1H), 3.55 ¨ 3.50 (m, 1H), 3.48 ¨ 3.40 (m, 3H), 2.56 ¨
2.52 (m, 1H).
According to the reaction route, Compound 33 (ammonium salt) was prepared from Compound 33-6 using the procedure for preparation of Compound 139.
The characteristic data of the Compound 33 was: MS (m/z): 1198.04[M-1]-. III
NMR (500 MHz, D20) 8 9.05 (s, 1H), 8.40 (s, 1H), 8.13 (s, 1H), 7.93 (s, 1H), 6.07 ¨ 6.03 (m, 1H), 6.01 (d, J= 5.5 Hz, 1H), 5.80 (d, J= 5.9 Hz, 1H), 5.78 (s, 1H), 5.45¨ 5.43 (m, 1H), 5.33 ¨ 5.30 (m, 1H), 4.93 ¨4.90 (m, 1H), 4.76 ¨ 4.75 (m, Date Recue/Date Received 2023-07-07 1H), 4.63 (d, J= 4.9 Hz, 1H), 4.50 (m, 1H), 4.48 (t, J= 4.5 Hz, 1H), 4.43 (m, 1H), 4.41 (t, J= 5.0 Hz, 1H), 4.33 (m, 1H), 4.29 - 4.27 (m, 2H), 4.24 - 4.22 (m, 1H), 4.19 - 4.18 (m, 2H), 4.07 -4.04 (m, 3H), 3.99 (s, 3H), 3.65 - 3.62 (m, 1H), 3.55 -3.52 (m, 1H), 3.43 (s, 3H), 2.61 -2.52 (m, 1H); 31P NMR (202 MHz, D20) 8 -0.93 (s, 1H), -11.65 (m, 2P), -22.90(m, 1P).
Example 28 Synthesis of Compound 151 TA- n-w o 'Y_: - il 0_, t?.- \ . "64, ,VG, r V
corni:,:virl 13111.3 .....rd Compound 151-1 õ...ir-i 47 - ,-,p::.und i11 N A, I ), .1 A 117 -- compaura ir. - ,,. 1. ?A:
PIKlehµe..)--CIA.: . sto,1 , ,....r.S, ,,,mi, _ ....r...p ,,, Ylc Aco , , , . µ ...J.
1 11,1Q - tl. Ph,,' Jr j....1 Compand 151-3 Ogeripei. I 1514 Cfminpatind 131-11 .1 ,.
1 - Atm irk.5,- .
POKAte), u' 1 641 _ ' i..4 '.'14 . .. PI-'h r : ., Dm I
, , ..,L 401 6t4s tbill 614 'IL\ "LiSt curnpound 151,6 Compound 1644 . Compound )1514 HIPCI4' TEA -u. HO -4 -041-0 tilith.LNAH2 HOI, Die i 1, 41-0.0C4telkditg, 4, 61-I 6ti TE CH
TEA t ' N1 Oortmound'-µ11$ 4 Compound 1414 08011 i H.
-itf 'WIC aoirp.o.
tAde, 04,1, DIM h1,r Hill a el `I'Ais 3N4( Flit 0=f1 _t N ..fli%ra ' H
'OH 4y i Compound 11,4" Compound 151. blk;.2 According to the reaction route, Compound 151-6 was prepared from Compound 139-3 using the procedure for preparation of Compound 139-10, except substituting iodoethane with bromobutane.
The characteristic data of Compound 151-6 was: III NMR (500 MHz, DMSO) 8:
10.60 (s, 1H), 7.99 (s, 1H), 6.45 (br, 2H), 5.70(s, 1H), 5.70 - 5.67 (d, J= 6.0 Hz, 1H), 5.03 -4.99 (t, J= 5.6 Hz, 1H), 4.41 -4.37 (m, 1H), 4.00 - 3.96 (m, 1H), 3.74 - 3.68 (m, 1H), 3.60 - 3.55 (m, 1H), 3.54 -3.48 (m, 1H), 3.44- 3.39 (m, 1H), 3.20(m, 2H), 2.58 - 2.52 (m, 1H), 1.57- 1.50 (m, 2H), 1.48- 1.45 (m, 2H), 0.88 (t, J= 6.5 Hz, 3H).

Date Recue/Date Received 2023-07-07 According to the reaction route, Compound 151(ammonium salt) was prepared from Compound 151-6 using the procedure for preparation of Compound 139.
The characteristic data of the Compound 151 was: MS (m/z): 1214.06[M- 1 ]. III
NMR (500 MHz, D20) 8 9.05 (s, 1H), 8.40 (s, 1H), 8.13 (s, 1H), 7.93 (s, 1H), 6.01 (d, J= 5.5 Hz, 1H), 5.80 (d, J= 5.9 Hz, 1H), 5.78 (s, 1H), 4.93 ¨4.90 (m, 1H), 4.76 ¨4.75 (m, 1H), 4.63 (d, J= 4.9 Hz, 1H), 4.50 (m, 1H), 4.48 (t, J= 4.5 Hz, 1H), 4.43 (m, 1H), 4.41 (t, J= 5.0 Hz, 1H), 4.33 (m, 1H), 4.29 ¨ 4.27 (m, 2H), 4.24 ¨ 4.22 (m, 1H), 4.19 ¨
4.18 (m, 2H), 4.07 ¨ 4.04 (m, 1H), 3.99 (s, 3H), 3.65 ¨3.62 (m, 1H), 3.55 ¨3.52 (m, 1H), 3.43 (s, 3H), 3.35 (t, J= 6.5 Hz, 2H), 2.61 ¨2.52 (m, 1H), 1.57¨ 1.50 (m, 2H), 1.48¨ 1.45 (m, 2H), 0.88 (t, J= 6.5 Hz, 3H);
31P NMR (202 MHz, D20) 8 -0.93 (s, 1H), -11.65 (m, 2P), -22.90 (m, 1P).
Example 29 Synthesis of Compound 51 o o !TrtrAm:ciozio.fom. _ Lt L.. Bel.TEA
. m ______________________ , liP
WOHIC '1 '1A-. NM. THF. )-1,15k. 3 NeaH4,Lle0H,,H,u, a 6C- e_t 4. 'II\
Mkt DV -nt.
OT 1,t (Ware 4fit'C
r r¨00414Xpuid 51-1 S Compound 51-2 o g CejcPb A Ph 4:1141 4 COOVOurld 11" c,N altit'l,"
,...., 0 .===='''''.'0.01 __. 112804, Ao20 811Ce."..0"434t ....5 'N-1NHAe I N NNN, will. .h,.,1014 54) 0 MOH, EA. 4060 1. aa,,, L.,,L.,._ 0, far¨ cd-- 2 TMEKI11, Plildle, 752C
SI¨Cr' Compound 51-3 Compotno 51-4 C' = 64nd 51-5 P 0 K:el:NH
JN:f,NH N NIH r.', De' 1 H ' 64 N':'''Fitf.H2 PC 15 H04 -0 N Nrfr'N). i . Fli 23/27. inidaD16,. N '--"( or-s55S 4 pommBh, D 0 TEA ,,H PP.. TEA DfilF r. --''' '101-I
40/..cri` ''61-1 cr-6 tql Compound 51-5 Compound 51-7 C rip, , rl 51-0 N f A, tr4H 2;4 11 NF

1' 4 TEA HOJ-0-Le=-=,(P-A
%__il' I N 1412 14*--12¨.DM26 Zak, OW Lt 61-k 61.4 . it ,Ati Au TEA#>.0,--'''' "b11 TEA ' bH1 Compound 51-9 C1011apo und El I -1 0 CI
rn.1-41.4:1 Fly,,,11(14 , 0 cf boo F11,7404 6 6 6 -,7CoNs o,"
ZrtC12. C11120. ri . HAj 2 We 4'.O4µ471H
Yl'IP
Nd.' bH NyNH
Compound 13g-15 j4/42 Compound 511 14 R2 According to the reaction route, Compound 51-6 was prepared from Compound 5-3 using the procedure for preparation of Compound 139-10, except substituting Compound 139-3 with Compound 5-3 and substituting iodoethane with bromopropyne.

Date Recue/Date Received 2023-07-07 The characteristic data of Compound 51-6 was: III NMR (500 MHz, DMSO) 8 10.60 (s, 1H), 8.01 (s, 1H), 6.46 (s, 211), 5.73 (s, 1H), 5.61 (d, J= 5.6 Hz, 1H), 5.03 (t, J= 5.3 Hz, 1H), 4.20 (t, J= 5.2 Hz, 1H), 4.15 (s, 2H), 3.90¨ 3.85 (m, 1H), 3.77 ¨ 3.71 (m, 1H), 3.58¨ 3.50 (m, 1H), 3.42 ¨ 3.35 (m, 2H), 3.32 (s, 1H), 2.34 ¨ 2.27 (m, 1H), 1.82¨ 1.69 (m, 1H), 1.59¨ 1.50 (m, 1H).
According to the reaction route, Compound 51 (ammonium salt) was prepared from Compound 51-6 using the procedure for preparation of Compound 139.
The characteristic data of the Compound 51 was: MS (m/z): 1210.04[M-1]. III
NMR (500 MHz, D20) 8 9.07 (s, 1H), 8.35 (s, 1H), 8.05 (s, 1H), 7.94 (s, 1H), 6.00 (d, J= 5.3 Hz, 1H), 5.80 (d, J= 5.2 Hz, 1H), 5.75 (s, 1H), 4.92 (m, 1H), 4.70 (t, J= 5.1 Hz, 1H), 4.49 -4.47 (m, 4H), 4.41 (m, 1H), 4.33 ¨ 4.29 (m, 2H), 4.26 ¨4.23 (m, 1H), 4.20 ¨ 4.18 (m, 3H), 4.12 ¨ 4.10 (m, 3H), 3.99 (s, 3H), 3.45 (m, 5H), 3.32 (s, 1H), 2.29 ¨
2.23 (m, 1H), 1.77¨ 1.65 (m, 2H); 31P NMR (202 MHz, D20) 8 -0.96 (s, 1H), -11.56 (m, 2P), -22.68 (m, 1P).
Example 30 Synthesis of Compound 163 >etr.O'41.... filaH, n-PrDr. THF. >etl:1"0 21,:vc, iv A : ,-1,-,i 6 0C -r,t, JFIC
Y'N'kfi..i0 Etzei TEA
jr,..
w.N.,,20.-.41' "ion 06,0-". . IX
Compound 5-3 Compound 163-1 OtingiVund 11634 0)1'1'4'h' ...I. f%
N, A A, o nir 4,-ri Compound 139 3 414.1114.10-1, '1) 11111 . 1-104 AGIO 114 Ac _________________________________________________________________ --r.
Eli. 1C r- 1 '13Itc am, u al T L. '. .. , 2-, 751'G _rdr¨

Opmpound 163-3 c,nrmuml 1634 Compound 163-5 NxiltH 0(j-NK 9 P Gb 1404-0 NANHI 1"811.t' imidszcie = r.'"'j 6No ,,,,,ar. N NI,H2 PC101dekv. cc TEA FIDN. TEA, Muff, Li. bH
_,..J. 'tii-i ti'l .=,,,P liCr Compound 1J63-,6 Compound 1J63-7 Compound =

, N, 1442pII I
õ24'RC14. TEA' NC1 -P-O ci -0 - ---**0.
()4,-pitil Mel Die - io I!
I ft= 0-1-"-.0-1.-0, 2h'-'-1.õ1"-"J117 a ' i 6H ,6H , ife_cr--l' bli I:2(4-J bH
CM Trr:I.ITId 16341 CO IROOLIn d 1i63,10 Ill'''''Ij-e"*'&14))114112 6' -11' ' ' ""1510101.e'''CiaPYIrNH2 0 p.' bmel'4k, 6 6 6 4, 1-1,_. = - = nt sY 'Dr&
N'''-'''''l 2,,c,.,,,,... _!:,, õ
5, ,..õ. Cii,...5.47...-N
NH
140" bpi ),,, Ho,' uoil yH
...wound 139-15 "47 Compound '163 14,H2 Date Recue/Date Received 2023-07-07 According to the reaction route, Compound 163-6 was prepared from Compound 5-3 rather than Compound 139-3 using the procedure for preparation of Compound 139-10, except substituting iodoethane with bromopropane.
The characteristic data of Compound 163-6 was: III NMR (500 MHz, DMSO) 8 10.60 (s, 1H), 8.01 (s, 1H), 6.46 (s, 211), 5.73 (s, 1H), 5.61 (d, J= 5.6 Hz, 1H), 5.03 (t, J= 5.3 Hz, 1H), 4.20 (t, J= 5.2 Hz, 1H), 3.90-3.85 (m, 1H), 3.77 ¨3.71 (m, 1H), 3.58¨ 3.50 (m, 1H), 3.42¨ 3.35 (m, 2H), 3.23 ¨ 3.20 (m, 2H), 2.34 ¨2.27 (m, 1H), 1.82¨ 1.69 (m, 1H), 1.59¨ 1.55 (m, 1H), 1.53 ¨ 1.50 (m, 2H), 0.88 (t, J= 6.5 Hz, 3H).
According to the reaction route, Compound 163 (ammonium salt) was prepared from Compound 163-6 using the procedure for preparation of Compound 139.
The characteristic data of the Compound 163 was: MS (m/z): 1214.04[M-1]-. NMR
(500 MHz, D20) 8 9.02 (s, 1H), 8.35 (s, 1H), 8.05 (s, 1H), 7.94 (s, 1H), 6.00 (d, J= 5.3 Hz, 1H), 5.80 (d, J= 5.2 Hz, 1H), 5.75 (s, 1H), 4.92 (m, 1H), 4.70 (t, J= 5.1 Hz, 1H), 4.49 -4.47 (m, 4H), 4.41 (m, 1H), 4.33 ¨ 4.29 (m, 2H), 4.26 ¨4.23 (m, 1H), 4.20 ¨ 4.18 (m, 3H), 4.12 ¨ 4.10 (m, 1H), 3.99 (s, 3H), 3.45 (m, 5H), 3.28 (t, J= 6.5 Hz, 2H), 2.29 ¨ 2.23 (m, 1H), 1.77¨ 1.65 (m, 2H), 1.55¨ 1.52 (m, 2H), 0.88 (t, J= 6.5 Hz, 3H); NMR (202 MHz, D20) 8 -0.96 (s, 1H), -11.56 (m, 2P), -22.68 (m, 1P).
Example 31 Synthesis of Compound 631 Date Recue/Date Received 2023-07-07 N xzNHil 0 N
0 xit,Nm <XII NH
N NJ-It TBECI. MINNOW Ill' 3.......Pr N 4'41442 P1/C, H2 TE190--...eLy NANH2 a 'IN"' H .
e , CNAF, Inds EA, e.L k INES
N.H. THP
0Bn 6en OH
Compound 1354 Compound 1131.1 Compound A31-2 -Irskx e--1 li .so-,t4r, IN' NHg NO`NNNIN N" DIHD POCI

s aHNTEA. TEA
e - _________w . TEA
k VMS THF, DMF, nt ( 17+1 P0(0M02. Et ( bH
0 .nc,P On? 0 me pH INDIANIAN 014 N 11 Caillowhil 6314 rA4 Compound G3 g-S
i /

e 1:11'x' rA 21 0 0 N*)' .!)'N N NI112 0 U
HO -P. -lt0 --C
FD
ISEPy, InA L ( dazola Hank TEA dH dN . Mel.W O -bk $ Ill PM% TEA. [INF. AI_ Owe &CID. [INF. r.i.
T EA o4, a /1411 Compound b3INE1 mu oomossod e31.7 i O

Ir',J r',0----0- .--N
,,,tH N 4,../ i ON.4' . N
11 . g by*
011.:-13-P7-0'"NO0^N N NHg 20212, MEd, At_ ON ON
.õ41F-oNs I.
TEA
pu "cr' .IIH Ny-Compound 631-8 Compound 13045 NN2 O
õ,.:1-7.1i "" '""'"o4-4-cr -W-13141142 411:1:11 HA rNO
C1/4)=() 3Elis. 0 NH \'`"rj...NW
HO'' 1H rinri Compound NI Nilt According to the above reaction route, Compound 135-6 (5 g, 12.91 mmol) was dissolved in DMF (50 mL), imidazole (4.39 g, 64.53 mmol) and TBSC1 (4.86 g, 32.27 mmol) were further added, and the mixture was stirred overnight at room temperature. After the reaction was completed, the reaction liquid was concentrated under reduced pressure to dryness. Ethyl acetate was added to dissolve the reaction product.
Then the product was successively washed with diluent hydrochloric acid, saturated sodium bicarbonate, and saturated saline, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to dryness, and purified by column chromatography to obtain 7.7 g of Compound 631-1.
10% Pd/C (1.00 g) was added to a solution of Compound 631-1 (7.7 g, 12.50 mmol) in ethyl acetate (100 mL), and the mixture was stirred overnight at room temperature under hydrogen atmosphere. Then, the Date Recue/Date Received 2023-07-07 reaction liquid was filtered by vacuum and the filtrate was concentrated under reduced pressure to obtain 6.2 g of Compound 631-2.
According to the reaction route, Compound 631-4 was prepared from Compound 631-2 using the procedure for preparation of Compound 6-4, except substituting acetyl chloride with methylaminoformyl chloride.
The characteristic data of Compound 631-4 was: III NMR (500 MHz, DMSO) 8:
10.60 (s, 1H), 7.99 (s, 1H), 6.45 (br, 211), 5.70 (s, 1H), 5.70 ¨ 5.67 (d, J= 6.0 Hz, 1H), 5.03 ¨4.99 (t, J= 5.6 Hz, 1H), 4.41 ¨4.37 (m, 1H), 4.00 ¨ 3.96 (m, 1H), 3.74¨ 3.68 (m, 1H), 3.60 ¨ 3.55 (m, 1H), 3.54¨
3.48 (m, 1H), 3.44¨ 3.39 (m, 1H), 2.76 (s, 3H), 2.58 ¨ 2.52 (m, 1H).
According to the reaction route, Compound 631(ammonium salt) was prepared from Compound 631-4 using the procedure for preparation of Compound 139.
The characteristic data of the Compound 631 was: MS (m/z): 1215.07[M-1]-. NMR
(500 MHz, D20) 8 9.05 (s, 1H), 8.40 (s, 1H), 8.13 (s, 1H), 7.93 (s, 1H), 6.01 (d, J= 5.5 Hz, 1H), 5.80 (d, J= 5.9 Hz, 1H), 5.78 (s, 1H), 4.93 ¨4.90 (m, 1H), 4.76 ¨4.75 (m, 1H), 4.63 (d, J= 4.9 Hz, 1H), 4.50 (m, 1H), 4.48 (t, J= 4.5 Hz, 1H), 4.43 (m, 1H), 4.41 (t, J= 5.0 Hz, 1H), 4.33 (m, 1H), 4.29 ¨ 4.27 (m, 2H), 4.24 ¨ 4.22 (m, 1H), 4.19 ¨
4.18 (m, 2H), 4.07 ¨ 4.04 (m, 1H), 3.99 (s, 3H), 3.65 ¨3.62 (m, 1H), 3.55 ¨3.52 (m, 1H), 3.43 (s, 3H), 2.68 (s, 3H), 2.61 ¨2.52 (m, 1H); 311) NMR (202 MHz, D20) 8 -0.93 (s, 1H), -11.65 (m, 2P), -22.90 (m, 1P).
Example 32 Synthesis of Compound 637 Date Recue/Date Received 2023-07-07 .0 N, Mel 1-1,.1-icrliEA, TEA
ni j N, ,,,H2 Terpsci, iimude TP.DPS0' ,a)*" I MIR AW
TBDPS=eNOINIAI'tiNNFI
______________________________________________ . .
L' 1h1F, r.i. ( 1-i Ogee THF, VC s=C bms II-IF, C(MF, m.
Compound 3.-6 Cca I ri I Iljfid am Concord 037-2 N NH 141)cm NILT4H
Hty'ssoo 1,1 N,H, POCki H 0 -ILO ="""µ-,/Lii).. N NH2. ySSPy mil derle i' 4-0-0===%.,0õ..N N, Nkõ, . _., .
FACIMIO)p, OPC TEA 64 i PPhj, l'cA,, Jr,u-', r.t N
M. vt. biAli ,0Me OM. Noe ,Comonund 637-3 r,,,p.,,,rd 16;374 Compound B37-5 0 , 0 A-4-1H.

.13P0.0A = H04-04-0 µ14 4^4 NI-1,1 Mei. DOIF. . 11 11 A . X
ZnICB2, 060, m CIFI 0FI, ..- 0.1p.c_,- , = .0 = N NK. +
a TEA kf brvlo CW6, TEA
arrolu Compound arpo Ctakpow-4 637-7 = =
0 N 3,¨NI-12 N.E.= ilõ 6 el, 6 ry Zn012, DIVASO, m, FIN ....roi $= H. N
0,....e d 'cli4B cr 3Ntl-tik' N
',,rP13-õ0 C', IN ILI
HO'' 'bEi N ,-,i-(IN He 6 VIN
Compound 1:24.15 "It -alumna' 637 Mg According to the reaction route, Compound 637-1 was prepared from Compound 3-6 using the procedure for preparation of Compound 6-1.
Compound 631-7 (9.8 g, 17.83 mmol) was dissolved in anhydrous THF (100 mL) at room temperature, and after the temperature was cooled to 0 C, Nail (1.07 g, 26.74 mmol) was gradually added. The mixture was stirred for 10 min, followed by addition of iodomethane (2.78 g, 19.61 mmol). After addition, the mixture was stirred for 5 hours at 0 C. Methanol (1 mL) and saturated ammonium chloride solution (150 mL) were then added. After addition ethyl acetate (150 mL), the solution was separated, and the organic phase was successively washed with water (100 mL *2) and saturated saline, dried over anhydrous sodium sulfate.
Subsequently, the organic phase was concentrated under reduced pressure and purified by column chromatography, to obtain 2.21 g of Compound 637-2.
The Compound 637-2(2.21 g, 3.92 mmol) was added to DCM (20 ml), and then TEA
(1 mL, 7.34 mmol) and TEA-311F (2.36 g, 14.68 mmol) were successively added. The mixture was stirred overnight at room temperature. HPLC detection showed that the raw materials were reacted completely. The solvent was removed by rotary evaporation. DCM was added to product, which was vigorously stirred. After filtration, a white solid was heated and vigorously stirred with Me0H (20 mL), and then the product was filtered and recrystallized with 10 mL of 1120(0.1 % TFA) to obtain 870 mg of Compound 637-3.

Date Recue/Date Received 2023-07-07 The characteristic data of Compound 637-3 was: III NMR (500 MHz, DMSO) 8:
10.60 (s, 1H), 7.99 (s, 1H), 6.45 (br, 2H), 5.70(s, 1H), 5.70 ¨ 5.67 (d, J= 6.0 Hz, 1H), 5.03 ¨4.99 (t, J= 5.6 Hz, 1H), 4.41 ¨4.37 (m, 1H), 4.00 ¨ 3.96 (m, 1H), 3.74¨ 3.68 (m, 1H), 3.60 ¨ 3.55 (m, 1H), 3.54¨
3.48 (m, 1H), 3.44¨ 3.39 (m, 1H), 3.26 (s, 3H), 3.20 (s, 3H), 2.58 ¨ 2.52 (m, 1H).
According to the reaction route, Compound 637 (ammonium salt) was prepared from Compound 637-3 using the procedure for preparation of Compound 139.
The characteristic data of the Compound 637 was: MS (m/z): 1186.04[M-1]. NMR
(500 MHz, D20) 8 9.05 (s, 1H), 8.40 (s, 1H), 8.13 (s, 1H), 7.93 (s, 1H), 6.01 (d, J= 5.5 Hz, 1H), 5.80 (d, J= 5.9 Hz, 1H), 5.78 (s, 1H), 4.93 ¨4.90 (m, 1H), 4.76 ¨4.75 (m, 1H), 4.63 (d, J= 4.9 Hz, 1H), 4.50 (m, 1H), 4.48 (t, J= 4.5 Hz, 1H), 4.43 (m, 1H), 4.41 (t, J= 5.0 Hz, 1H), 4.33 (m, 1H), 4.29 ¨ 4.27 (m, 2H), 4.24 ¨ 4.22 (m, 1H), 4.19 ¨
4.18 (m, 2H), 4.07 ¨ 4.04 (m, 1H), 3.99 (s, 3H), 3.65 ¨3.62 (m, 1H), 3.55 ¨3.52 (m, 1H), 3.43 (s, 3H), 3.32 (s, 3H), 3.23 (s, 3H), 2.61 ¨2.52 (m, 1H); 31P NMR (202 MHz, D20) 8 -0.93 (s, 1H), -11.65 (m, 2P), -22.90 (m, 1P).
Example 33 Synthesis of Compound 215 r, (Njl,,,,,,N)k 0 0 <411 Ho Ne NH,2 CiNi 04-0 $ 0 _ N NH2 459C f5H
TF,4, 151-1 urvlo TEA lime Lim :::ompc=irld 3-8 Compound 215-1 cV
+Nin 0 0 0 0 pralk) In4-16-014 pr u btie ZnC12, DMSO, r.t. HO - - 44, blvle '11:74+1afl 3NH4' d '4%tp rr"41)-\r4 tuf N
N'yNjk Compc,ffid elliripPond 215 NH2 According to the reaction route, Compound 215 (ammonium salt) was prepared from Compound 3-9 using the procedure for preparation Compound 139, except substituting iodomethane with bromotoluene.
The characteristic data of the Compound 215 was: MS (m/z): 1248.07[M- l]. NMR
(500 MHz, D20) 8 8.37 (s, 1H), 8.07 (s, 1H), 7.96 (s, 1H), 7.49 ¨ 7.44 (m, 5H), 5.93 - 5.97 (m, 3H), 5.74 (d, J= 6.2 Hz, 1H), 5.66 (d, J= 3.8 Hz, 1H), 4.81 (d, J= 23.6 Hz, 2H), 4.48 (d, J= 4.2 Hz, 1H), 4.42 (s, 1H), 4.38 (d, J= 4.6 Hz, 1H), 4.35 (s, 1H), 4.29 ¨4.21 (m, 3H), 4.20 ¨ 4.12 (m, 2H), 4.09 (d, J= 15.0 Hz, 3H), 4.01 (s, 3H), 3.65 ¨

Date Recue/Date Received 2023-07-07 3.62 (m, 1H), 3.55 ¨ 3.52 (m, 1H), 3.43 (d, J= 9.3 Hz, 311), 3.39 (s, 311), 2.55 ¨2.50 (m, 1H);31P NMR (202 MHz, D20) 8 -0.98 (s, 1P), -11.76- (m, 2P), -23.23 (m, 1P).
Example 34 Synthesis of Compound 181 ow II¨ IN-13-0'''µ.vOro N#I'''NH, Harn, TEA i., HO 101_0,...ii 'fermi/
26_41...,,it.tr..:' ONan n ZhCnini. D',1F. Li 6H 614 . r 1. '& oii tilalik TEA 011 TEA ,,,bw comeouwid 34 Compound idl -1 Compound 1131-fmN IN
1,., NH?
c,,,,,,,,,,,,vr ,-, .bme".."" - - "
%Mo. a HA '" m, -. , .p.! -3N1H,0" d 'c' Hd: 'bH F4 Y4H H..), )II-.
II y Nil COMPUnd 13,24-15 NH 2 Compound' 1811 itnjH2 According to the reaction route, Compound 181 (ammonium salt) was prepared from Compound 3-8 using the procedure for preparation of Compound 139, except substituting phosphoric acid with thiophosphoric acid.
The characteristic data of the Compound 181 was: MS (m/z): 1188.08[M-1]-. 111 NMR (500 MHz, D20) 8 9.05 (s, 1H), 8.40 (s, 1H), 8.13 (s, 1H), 7.93 (s, 1H), 6.01 (d, J= 5.5 Hz, 1H), 5.80 (d, J= 5.9 Hz, 1H), 5.78 (s, 1H), 4.93 ¨4.90 (m, 1H), 4.76 ¨4.75 (m, 1H), 4.63 (d, J= 4.9 Hz, 1H), 4.50 (m, 1H), 4.48 (t, J= 4.5 Hz, 1H), 4.43 (m, 1H), 4.41 (t, J= 5.0 Hz, 1H), 4.33 (m, 1H), 4.29 ¨ 4.27 (m, 2H), 4.24 ¨ 4.22 (m, 1H), 4.19 ¨
4.18 (m, 2H), 4.07 ¨ 4.04 (m, 1H), 3.99 (s, 3H), 3.65 ¨3.62 (m, 1H), 3.55 ¨3.52 (m, 1H), 3.43 (s, 3H), 3.32 (s, 3H), 2.61 ¨2.52 (m, 1H); 31P NMR (202 MHz, D20) 8 29.38 (m, 1P), -0.94 (s, 1H), -11.58 (m, 2P).
Example 35 Synthesis of Compound 547 . _ iiw1 Q
mci-P-1)4:- 'y(' . umb 1 IN
ow croila znaz ... h;,N
Le I r I 1"1H t ( ..6 ,N1Hz /6b,r,õ10 el ek LIMSO, 1'1 y'---r HO"
Oppripound i 12 all Ilcod 'mid Ml According to the reaction route, Compound 547 (ammonium salt) was prepared from Compound 3-10 and Compound 547-1 using the procedure for preparation of Compound 139.
The characteristic data of the Compound 547 was: MS (m/z): 1188.08[M-1]-. 111 NMR (500 MHz, D20) 8 9.05 (s, 1H), 8.40 (s, 1H), 8.13 (s, 1H), 7.93 (s, 1H), 6.01 (d, J= 5.5 Hz, 1H), 5.80 (d, J= 5.9 Hz, 1H), 5.78 (s, 1H), 4.93 ¨4.90 (m, 1H), 4.76 ¨4.75 (m, 1H), 4.63 (d, J= 4.9 Hz, 1H), 4.50 (m, 1H), 4.48 (t, J= 4.5 Hz, Date Recue/Date Received 2023-07-07 HD, 4.43 (m, 111), 4.41 (t, J = 5.0 Hz, 1H), 4.33 (m, 1H), 4.29 - 4.27 (m, 2H), 4.24 - 4.22 (m, 1H), 4.19 -4.18 (m, 2H), 4.07 - 4.04 (m, 1H), 3.99 (s, 3H), 3.65 -3.62 (m, 1H), 3.55 -3.52 (m, 1H), 3.43 (s, 3H), 3.32 (s, 3H), 2.61 - 2.52 (m, 1H); 31P NMR (202 MHz, D20)3 7.55 (m, 1P), -0.93 (s, 1H), -11.60 (m, 1P), -23.02 (m, 1P).
Example 36 Synthesis of Compound 199 rcti,õ, NH, 0 rito-0 ao dN
tM d 'Time "." d "WEI ' pool, I ZiON19)3 TEA
PVSSPY.
or F'Pha, TE&DAF.rt HOs' N kr NH , Hce ;LL-I
bH N .
NI42 NIFI2 NfH2 COMPOtind 19961 Compo.. rid 19Y-2 CiiwJ19!.I
A ?j 0 10 0 HO -P -3-'00"-' y1/41 zna2, mso, Lt.
H
6HINb,. NH FII2N Pok9O 204114+
/FA NOMe 11 Compound 340 HO' NI
C011wpciund According to the above synthetic route, Compound 199-1 (250 mg, 0.43 mmol) was dissolved in trimethyl phosphate (7.5 mL), and phosphorus oxychloride (0.40 mL, 4.30 mmol) was added at 0 C. After the mixture was reacted overnight, a small amount of raw materials was remained. Water was added to quench the reaction, and the liquid was directly passed through ion exchange column to collect a peak of the desirable product. Then, the collected liquid was concentrated and passed through reversed phase column to obtain the product, which was concentrated and freeze-dried to obtain 192 mg of Compound 199-2 (triethylamine salt).
The Compound 199-2 (192 mg, 0.29 mmol), imidazole (99 mg, 1.46 mmol), 2,2'-dithiobipyridine (128 mg, 0.58 mmol), N,N-dimethylformamide (2 mL), and triethylamine (40 !IL, 0.29 mmol) were added to a reaction flask, followed by addition of triphenylphosphine (152 mg, 0.58 mmol) under stirring. The mixture was stirred for 2 hours at room temperature under nitrogen atmosphere. After the reaction was completed, the reaction system was added to a mixture solution of sodium iodide (218 mg, 1.45 mmol) and acetone (5 mL), stirred for 10 min at room temperature. The liquid was filtered and the filter cake was washed with acetone. Subsequently, the filter cake was collected and dried at room temperature under reduced pressure to obtain 210 mg of Compound 199-3.

Date Recue/Date Received 2023-07-07 Compound 199 (ammonium salt) was prepared from Compound 3-10 and Compound 199-3 using the procedure for preparation of Compound 139.
The characteristic data of the Compound 199 was: MS (m/z): 1122.06[M-1]. 111 NMR (500 MHz, D20) 8 8.22 (s, 111), 7.91 (br, 211), 5.98 (s, 111), 5.86 (s, 111), 5.75 (s, 111), 5.13 (s, 111), 4.92 (d, J= 7.0 Hz, 1H), 4.68 (m, 1H), 4.47 (m, 2H), 4.41 (m, 1H), 4.36 ¨4.32 (m, 6H), 4.19 ¨4.13 (m, 4H), 4.04(s, 3H), 3.88- 3.84 (m, 1H), 3.80- 3.77 (m, 1H), 3.51 (s, 3H), 3.46 (s, 3H), 2.58 ¨ 2.53 (m, 1H);31P NMR (202 MHz, D20) 8 -11.13 (m, 1P), -11.70 (d, J= 19.2 Hz, 1P), -23.12 (t, J= 19.2 Hz, 1P).
Example 37 Synthesis of Compound 201 1,10-3-0 tsmer4''," 4, ,t,r46 6NA.
Poch Peg1,40,3 AEA FINI PytSPy ,,nkraere PR TEA 1)fticliCIY
DAtIF,ri OH Ho bpi 4,(1-1 "re 11H PLI)F1 Compound 201-2 Compound 201-1 Clompoind 201-2 ZI ri sin (214 pri,6,N112 2t412. EIMSO, TEA SamabH
J Me 2HH4*
NH, Ca0p0Und 3,10 Compound /01t According to the reaction route, Compound 201 (ammonium salt) was prepared from Compound 201-1 using the procedure for preparation of Compound 139.
The characteristic data of the Compound 201 was: MS (m/z): 1133.03[M-1]. 1H
NMR (500 MHz, D20) 8 9.14 (s, 1H), 8.42 (s, 1H), 8.24 (s, 1H), 7.82(s, 1H), 6.18 (s, 1H), 5.82 (d, J= 3.8 Hz, 1H), 5.68 (d, J= 5.3 Hz, 1H), 4.72 ¨ 4.71 (m, 1H), 4.56 (t, J= 5.1Hz, 1H), 4.46 ¨4.42 (m, 3H), 4.31 ¨4.19 (m, 4H), 4.15 (t, J=
4.3 Hz, 1H), 4.04 (s, 3H), 4.00 (m, 1H), 3.73 ¨3.69 (m, 2H), 3.58 ¨ 3.53 (m, 5H), 3.50 (s, 3H), 2.89 ¨2.87 (m, 1H), 2.61 ¨2.53 (m, 3H);31P NMR (202 MHz, D20) 8 -11.52 (m, 2P), -22.88 (t, J= 18.6 Hz, 1P).
Example 38 Synthesis of Compound 203 Date Recue/Date Received 2023-07-07 H0J-0,--Cr .-ey ' ,, 1:1_ N ---"-1 INTO P 114 P4 d bet '-'.' 0 Del ----= a 04.0 pock, Nry Cr. 11 P0(004919 TEA 7-_,I1 PASIly, linlebtattie d 117"r48 at pm. TEA, 06/IF. Lt.
''''''Ct'Cr'Ll mco ,Emti IN ,e., K Ide ." N, -NH
HO iiii y 14/42 ln.44,, NI1.4 CUM paind 203-1 Compound 203-2 Compound 203-3 41_ Ol=41 r ,3:: HI N El _ e bEL N 4,v.I
4, 04 ...CI 43 ..,0 -'1....00.1µ4 - ,pq t,14.12 ZnOl?, DMSO, LL
-. -.
i. 1.1,A hite C1/4.Tet _ 61-I &I 31.4144' d ..1 mi.
He Compound 3,10 Compound VA
According to the reaction route, Compound 203 (ammonium salt) was prepared from Compound 203-1 using the procedure for preparation of Compound 139.
The characteristic data of the Compound 203 was: MS (m/z): 1186.02[M-1]. III
NMR (500 MHz, D20) 8 9.05 (s, 1H), 8.40 (s, 1H), 8.13 (s, 1H), 7.93 (s, 1H), 6.01 (d, J= 5.5 Hz, 1H), 5.80 (d, J= 5.9 Hz, 1H), 5.78 (s, 1H), 4.93 ¨4.90 (m, 1H), 4.76 ¨4.75 (m, 1H), 4.63 (d, J= 4.9 Hz, 1H), 4.50 (m, 1H), 4.48 (t, J= 4.5 Hz, 1H), 4.43 (m, 1H), 4.41 (t, J= 5.0 Hz, 1H), 4.33 (m, 1H), 4.29 ¨ 4.27 (m, 2H), 4.24 ¨ 4.22 (m, 1H), 4.19 ¨
4.18 (m, 2H), 4.07 ¨ 4.04 (m, 1H), 3.99 (s, 3H), 3.65 ¨ 3.62 (m, 1H), 3.55 ¨3.52 (m, 1H), 3.40 (q, J= 6.5 Hz, 2H), 3.32 (s, 3H), 2.61 ¨2.52 (m, 1H), 1.18 (t, J= 6.5 Hz, 3H); 31P NMR
(202 MHz, D20) 8 -0.93 (s, 1H), -11.65 (m, 2P), -22.90 (m, 1P).
Example 39 Synthesis of Compound 639 Date Recue/Date Received 2023-07-07 cii 0 in, (1,'* clAN- N NIN
.111)1:,NIFI cj 1 A
Thapso,õ....cy.N I re.õ,14.12 ___,Iõ_. ThDpsce".44.Oro.,1- :A - -NH2 VriFfTEA, TEA . 1-10"'Nf.y N NF1 ,1.: Oli INN 4kIN

N1H2 Oli_ Compound 6-2 / Crifrobund IM-1 Compound 6394 NflAH N XLT,44 Fwa N NH
PISSPY, bill''''7010 r T4-P-O''''''.4)eN NF NH2 HBPO, TEA
u .
P0110Mins, WC TEA ON ,---.( PPh3, Tti. Li .,11 , Li - oNia , ZoC12, 064F n r t, HH ,JH
Compound 63963 I"- Compound P 1 NH HO-5101V44'eLiN 1 'NANN9 M4511" CINAF
6H 6N a 6 PH OH I-2 TEA ,i)41 't7H TEA

COmpoti id 63665 Comp, , 9ri YOkin z.cp a N2N N -.101k15 '144"ty,N10 NO" '61,1 N)*NN Roo' .64 N,,T,Niff Compound 11.4-15 NH, Compound 639 NH2 According to the reaction route, Compound 639-2 was prepared from Compound 6-2 using the procedure for preparation of Compound 6-4, except substituting acetyl chloride with dimethylcarbamoyl chloride.
The characteristic data of the Compound 639-2 was: III NMR (500 MHz, DMS0)6 10.58 (s, 1H), 8.03 (s, 1H), 6.50- 6.49(m, 311), 6.00 (d, J= 3.4 Hz, 1H), 5.73(s, 1H), 5.14 (t,J=
4.8 Hz, 1H), 4.14(s, 1H), 3.91 (d, J= 9.8 Hz, 1H), 3.78 - 3.76 (m, 1H), 3.56 - 3.54 (m, 1H), 3.08 ¨ 3.03 (m, 1H), 2.76 (s, 6H), 2.45 ¨2.40 (m, 1H).
According to the reaction route, Compound 639 (ammonium salt) was prepared from Compound 639-2 using the procedure for preparation of Compound 139.
The characteristic data of the Compound 639 was: MS (m/z): 1228.06[M-1]. III
NMR (500 MHz, D20) 8 9.08 (s, 1H), 8.46 (s, 1H), 8.20 (s, 1H), 7.98 (s, 1H), 6.07 (d, J= 5.3 Hz, 1H), 5.86 (s, 1H), 5.83 (d, J= 5.9 Hz, 1H), 4.97 ¨ 4.94 (m, 1H), 4.76 ¨ 4.75 (m, 1H), 4.63 (d, J= 4.4 Hz, 1H), 4.54 ¨4.50 (m, 3H), 4.46 (t, J= 4.9 Hz, 1H), 4.38 (m, 1H), 4.35 ¨4.33 (m, 2H), 4.29 ¨4.26 (m, 1H), 4.24 ¨ 4.20 (m, 2H), 4.17 ¨
4.14 (m, 1H), 4.03 (s, 3H), 3.53 (dd, J1= 14.0 Hz, J2 = 8.1 Hz, 1H), 3.47 (s, 3H), 3.29 (m, dd, J1= 14.0 Hz, Date Recue/Date Received 2023-07-07 J2= 6.1 Hz, 1H), 2.99 (s, 6H), 2.64 ¨ 2.59 (m, 1H); 31P NMR (202 MHz, D20)3 -0.95 (s, 1H), -11.49 (d, J=
10.9 Hz, 1P), -11.58 (d, J= 12.0 Hz, 1P), -22.82 (t, J= 18.2 Hz, 1P).
Example 40 Synthesis of Compound 323 N lAr,ivi arAttem NIANH
o I (1J 01-1 ,o,N NH ii., ('' I Imps , ,N, -..4i winTrA. TEA IHI00.11- N' NiH2 Teopsomfy-N NinHz THF, INF, r.t. e .,, py, OCIA, VC , , s:
H
NH =(, 0 blVlo Me coil [I jr,,, 1 õ.2 Compound 3234 Compound 323-2 14 1)1.--NH
9 ' 0 õAõ. 0 fl,alliLtre,1 PYP1 imida7nle PP,11A. [PA I I TEA ..
F.-.. ,, ...õ,pc ILA all .
!)...E. I --- &la '-1/2*-04 Znc17., LOP, rt.
( 'b.+ e b Nil \ 11 0 o oINH
rou , MG
Compound 3234 Coompound 3234 %
HO-Lo-Laa'4Ø1N NrANR, 1AM' NIF'43-0r4 r 1 a TEA ( bH TEA ? bH
\
0,411H 0*eH
eMe We CnfrIpound 325-5 compound a2:3,5 *41-D--teN' Cr 0 0 0 cf ''ONat ZrenIJ?, GIMSCI, u. II, H2N HIN
'15 priN 3NH,"
Nlec?
z H'Cr' -bil NI.fitH 1-1t1 '.611 14 ty"' Compound 13945 NH, ' Compo.ind S73 WI
According to the reaction route, Compound 323-2 was prepared from Compound 6-2 using the procedure for preparation of Compound 6-4, except substituting acetyl chloride with methylclhlorofonmate.
The characteristic data of the Compound 323-2 was: III NMR (500 MHz, DMSO) 8 10.60 (s, 1H), 7.98 (s, 1H), 7.04 (s, 1H), 6.47 (s, 2H), 5.71 (s, 1H), 5.64 (d, J= 4.9 Hz, 1H), 5.06 (t, J= 4.8 Hz, 1H), 4.38 (s, 1H), 3.92 (d, J= 8.8 Hz, 1H), 3.69 (d, J= 8.8 Hz, 1H), 3.63 (s, 3H), 3.53 -3.49 (m, 1H), 3.30¨ 3.24 (m, 1H), 3.13 ¨ 3.06 (m, 2H), 2.49 - 2.46 (m, 1H).
According to the reaction route, Compound 323 (ammonium salt) was prepared from Compound 323-2 using the procedure for preparation of Compound 139.
The characteristic data of the Compound 323 was: MS (m/z): 1215.08[M-1]-. III
NMR (500 MHz, D20) 8 9.00 (s, 1H), 8.38 (s, 1H), 8.10 (s, 1H), 7.95 (s, 1H), 6.01 (d, J= 5.6 Hz, 1H), 5.81 ¨5.80 (m, 2H), 4.93 -Date Recue/Date Received 2023-07-07 4.90 (m, 1H), 4.76 ¨4.74 (m, 1H), 4.62 (d, J = 4.2 Hz, IH), 4.50 ¨4.46 (m, 3H), 4.40 (t, J = 5.0 Hz, 111), 4.34-4.22 (m, 4H), 4.21-4.16 (m, 211), 4.12 ¨4.09 (m, 111), 3.99 (s, 3H), 3.63 (s, 3H), 3.43 ¨3.38 (m, 4H), 3.25 ¨ 3.21 (m, 111), 2.57 ¨ 2.52 (m, 111); 31P NMR (202 MHz, D20) 8 -0.98 (s, 111), -11.55 (m, IP), -22.73 (m, IP).
Example 41 Synthesis of Compound 641 o 0 NXIILNH
Nfo NH N 1.,111---NH 4.'1.4 I 0,1õ
NH, i 11-1F:TFA. A
c I * HO--4"& N NH2 TIMPSO"--41-00 N NH2 Me TEDPS/01."NO-.) 14 'NH2 TE
S. ,-11,1 THE. in C ;11:111% THF, ME, r11, NHAc IOW
Compound 4-2 Compound J641-1 Nx111.-Null N
POC13 HO-A--ON 14 N1-12 PySSPOH y.
jrni14.a7rAn ,1--- 'N-0-0 ' N N NH2 PPI. TEA , F31.F,.r,;',:.-2'.".?' 1130pMehy, WC z? boa, igkuk. ;,., bblo NHAc clwriPmild 641: Na-IN H2 Compound 641-4 r1õ

X
NH
0 0 IH)PO4, TEA = Ho j_c, .1:4! ., 0......ØA 4-;"---, mo, M 0 r Zne12, ()kW, 4-04-0-'%--cf)-.N NF
NH2 4.
6H 011 .
TEA
TEA \S' 'brills, INHAo NHAc Compound 641-5 Compo..wri 641-6 0 hi NH2 0 0 0 0Na ..t. '.. Ns. ,.N6 6 6 =
' N --, l'4 Mo0 -P ZnC12, DIASOI, t 1, . H21- AcH, U d ...
.T=N aNI-14*
N6....cylW) L j ....-,,.----!
fid rtH til,Nifi Ha bli NNH
cummvo in-15 NF12. Compound 641 Nit, According to the reaction route, Compound 641-2 was prepared from Compound 6-3 using the procedure for preparation of Compound 637-3.
The characteristic data of the Compound 641-2 was: 11-1 NMR (500 MHz, D20) 6 9.07 (s, IH), 5.99 (s, 1H), 4.64 (d, J= 4.5 Hz, 1H), 4.21 (d, J= 10.6 Hz, 1H), 3.96 (d, J= 13.1 Hz, 1H), 3.69 (dd, J= 13.2, 3.4 Hz, 1H), 3.40 (dd, J= 14.2, 8.7 Hz, 1H), 3.27 (dd, J= 14.1, 5.8 Hz, 1H), 3.22 (s, 3H), 2.56 - 2.40 (m, 1H), 1.89 (s, 3H).
According to the reaction route, Compound 641 (ammonium salt) was prepared from Compound 641-2 using the procedure for preparation of Compound 139.

Date Recue/Date Received 2023-07-07 The characteristic data of the ammonium salt of Compound 641 was: MS (m/z):
1213.05[M-1]-. 111 NMR (500 MHz, D20) 8 9.08 (s, 1H), 8.46 (s, 1H), 8.20 (s, 1H), 7.98 (s, 1H), 6.07 (d, J= 5.3 Hz, 1H), 5.86 (s, 1H), 5.83 (d, J= 5.9 Hz, 1H), 4.97 ¨ 4.94 (m, 1H), 4.76 ¨4.75 (m, 1H), 4.63 (d, J= 4.4 Hz, 1H), 4.54 ¨
4.50 (m, 3H), 4.46 (t, J= 4.9 Hz, 1H), 4.38 (m, 1H), 4.35 ¨4.33 (m, 2H), 4.29 ¨ 4.26 (m, 1H), 4.24 ¨ 4.20 (m, 2H), 4.17 ¨ 4.14 (m, 1H), 4.03 (s, 3H), 3.53 (dd, J,= 14.0 Hz, J2 = 8.1 Hz, 1H), 3.47 (s, 3H), 3.41 (s, 3H), 3.29 (m, dd, J1= 14.0 Hz, J2 = 6.1 Hz, 1H), 2.64 ¨ 2.59 (m, 1H), 2.00 (s, 3H);
31P NMR (202 MHz, D20) 8 -0.95(s, 1H), -11.49 (d, J= 10.9 Hz, 1P), -11.58 (d, J= 12.0 Hz, 1P), -22.82 (t, J= 18.2 Hz, 1P).
Example 42 Synthesis of Compound 337 XI
113PS%. TEA HO j_oic 6NO 7110?õ DMF, 6H 6H N NN4 P.161IF
1.11C;t1"- i:JHA.?1 r'l. um LAI
TEA Lbei convoanxi 4 Corrpaund 337-1 Compound 337-2 mn, 1--14 1W4' ''.N10-11-0-Y1-0Yr2 arta ' 14.4V' H 6 9 iS
d bop omso, a 3N -I, II 'CI
1/4),.0?clito l'Y-2.4r14Yr fb, Coripound 13E115 Nfri" Compecnid 337 JNH
According to the reaction route, Compound 337 (ammonium salt) was prepared from Compound 6-6 using the procedure for preparation of Compound 139, except substituting phosphoric acid with thiophosphoric acid.
The characteristic data of the Compound 337 was: MS (m/z): 1215.05[M-1]-. 111 NMR (500 MHz, D20) 8 9.08 (s, 1H), 8.46 (s, 1H), 8.20 (s, 1H), 7.98 (s, 1H), 6.07 (d, J= 5.3 Hz, 1H), 5.86 (s, 1H), 5.83 (d, J= 5.9 Hz, 1H), 4.97 ¨ 4.94 (m, 1H), 4.76 ¨ 4.75 (m, 1H), 4.63 (d, J= 4.4 Hz, 1H), 4.54 ¨ 4.50 (m, 3H), 4.46 (t, J=
4.9 Hz, 1H), 4.38 (m, 1H), 4.35 ¨4.33 (m, 2H), 4.29 ¨ 4.26 (m, 1H), 4.24 ¨4.20 (m, 2H), 4.17 ¨ 4.14 (m, 1H), 4.03 (s, 3H), 3.53 (dd, J1= 14.0 Hz, J2 = 8.1 Hz, 1H), 3.47 (s, 3H), 3.29 (m, dd, J1= 14.0 Hz, J2 = 6.1 Hz, 1H), 2.64 ¨ 2.59 (m, 1H), 2.00(s, 3H); 31P NMR (202 MHz, D20)3 28.84(m, 1P), -0.96 (s, 1H), -11.55 (m, 2P).
Example 43 Synthesis of Compound 561 Date Recue/Date Received 2023-07-07 earN

ACID frVJ knAl d'vPia ert TEA
H 43'"L 15H
compoim 5d0-1 Compouna 351 According to the reaction route, Compound 561 (ammonium salt) was prepared from Compound 6-8 and Compound 547-1 using the procedure for preparation of Compound 139.
The characteristic data of the Compound 561 was: MS (m/z): 1215.05[M-1]. NMR
(500 MHz, D20) 8 9.08 (s, 1H), 8.46 (s, 1H), 8.20 (s, 1H), 7.98 (s, 1H), 6.07 (d, J= 5.3 Hz, 1H), 5.86 (s, 1H), 5.83 (d, J= 5.9 Hz, 1H), 4.97 ¨ 4.94 (m, 1H), 4.76 ¨ 4.75 (m, 1H), 4.63 (d, J= 4.4 Hz, 1H), 4.54 ¨ 4.50 (m, 3H), 4.46 (t, J
= 4.9 Hz, 1H), 4.38 (m, 1H), 4.35 ¨4.33 (m, 2H), 4.29 ¨4.26 (m, 1H), 4.24 ¨
4.20 (m, 2H), 4.17 ¨4.14 (m, 1H), 4.03 (s, 3H), 3.53 (dd, Ji = 14.0 Hz, J2= 8.1 Hz, 1H), 3.47 (s, 3H), 3.29 (m, dd, J1= 14.0 Hz, J2= 6.1 Hz, 1H), 2.64 ¨ 2.59 (m, 1H), 2.00 (s, 3H); 31P NMR (202 MHz, D20) 8 7.58 (m, 1P), -0.95 (s, 1H), -11.55 (d, J= 10.9 Hz, 1P), -23.34 (m, 1P).
Example 44 Synthesis of Compound 118 fft4 ok:r.),NIN

[ [ NH ONt. d /Not N.Att.elq I logYa 52;c41-(117 1-4:7-"'õe.:: brdN171:1X1142614 0-5-0-LV'iry-41 NANHI, "'Loma MCI
6H lino:0%r DrAso, r.i. TAW
TEA bH
NOM.
HO" = 0, N
bH
CAMICILInd 8,8 Compound 110-1 au oh pound According to the reaction route, Compound 118 (ammonium salt) was prepared from Compound 6-8 using the procedure for preparation of Compound 139, except substituting Compound 139-15 with Compound 110-1.
The characteristic data of the Compound 118 was: MS (m/z): 1160.07[M-1]. NMR
(500 MHz, D20) 8 9.08 (s, 1H), 8.46 (s, 1H), 8.20 (s, 1H), 7.86 (d, J= 8.1 Hz, 1H), 6.07 (d, J= 5.3 Hz, 1H), 5.86 (s, 1H), 5.83 ¨ 2.80(m, 2H), 4.97 ¨ 4.94 (m, 1H), 4.76 ¨4.75 (m, 1H), 4.63 (d, J= 4.4 Hz, 1H), 4.54 ¨ 4.50 (m, 3H), 4.46 (t, J= 4.9 Hz, 1H), 4.38 (m, 1H), 4.35 ¨4.33 (m, 2H), 4.29 ¨4.26 (m, 1H), 4.24 ¨4.20 (m, 2H), 4.17 ¨4.14 (m, 1H), 4.03(s, 3H), 3.53 (dd, J, 14.0 Hz, J2= 8.1 Hz, 1H), 3.47(s, 3H), 3.29(m, dd, J, 14.0 Hz, J2=
6.1 Hz, 1H), 2.64 ¨ 2.59 (m, 1H), 2.00 (s, 3H); NMR (202 MHz, D20)3 -0.95 (s, 1H), -11.49 (d, J= 10.9 Hz, 1P), -11.58 (d, J= 12.0 Hz, 1P), -22.82 (t, J= 18.2 Hz, 1P).
Example 45 Synthesis of Compound 329 Date Recue/Date Received 2023-07-07 No\ ? H2 Y yytH, N ,-110 0 '(.: ,-, 4141,4,NH r)Na 0+0 - ItimeN4k,,, ---r NH Nao,"

H : 14 -ri'",,C...),,r1N - N"Nk2 . -P -0 ''''...00=N

I
Mel, INAF ' r=N
' OH + 4 r.t. , TE:, \
NIHAG NH Atõ MYR in4 N
C..),,voLnd 5-5 C,VvoLrld 329-1 NIH2 Cdthiptdrui 17S-3 41n.
no ,p), 6 6 (5 L
._ .164 bm.-- i 07,6 zilch. DMSO. Lit, H2N AoHIN
sr Mlle )1*Nr_ y)---i"
HO' 012n2p63ultil 829 According to the reaction route, Compound 329 (ammonium salt) was prepared from Compound 6-5using the procedure for preparation of Compound 173.
The characteristic data of the Compound 329 was: MS (m/z): 1197.07[M-1]. III
NMR (500 MHz, D20) 8 9.08 (s, 1H), 8.46 (s, 1H), 8.20 (s, 1H), 7.98 (s, 1H), 6.07 (d, J= 5.3 Hz, 1H), 5.86 (s, 1H), 5.83 (d, J= 5.9 Hz, 1H), 4.97 ¨4.94 (m, 1H), 4.76 ¨ 4.75 (m, 1H), 4.63 (d, J= 4.4 Hz, 1H), 4.54¨ 4.50 (m, 3H), 4.46 (t, J=
4.9 Hz, 1H), 4.38 (m,1H), 4.35 ¨4.33 (m, 2H), 4.29 ¨ 4.26 (m, 1H), 4.24 ¨ 4.20 (m, 2H), 4.17 ¨ 4.14 (m, 1H), 4.03 (s, 3H), 3.53 (dd, Ji = 14.0 Hz, J2 = 8.1 Hz, 1H), 3.47 (s, 3H), 3.29 (m, dd, J1= 14.0 Hz, J2 = 6.1 Hz, 1H), 2.64 ¨ 2.59 (m, 1H), 2.47 (t, J= 20.4 Hz, 2H), 2.00 (s, 3H); 31P NMR
(202 MHz, D20) 8 16.79 (s, 1P), 7.80 (dd, J= 25.4, 6.8 Hz, 1P), -0.95 (s, 1H), -11.49 (d, J= 10.9 Hz, 1P).
Example 46 Synthesis of Compound 345 \
= /'.-IANH 0 pA NI:11-1õ41 sit,,,, ipitiartai o r Ni-p-0J-0-6,,or , :c, I ek C.MI OH 44, N.-- = , 1 4, TEA .11.. 11.1 µIMAt PPh3n TEA, MolF¶ a 9: CNa )4407 Cbmround 6-9 Cornpotod 345,4 HO --g -04, -.0yj.-TLN142 0 0 0 0 l'44 04-01-04-04-0i Ol 15148 TEA Zn012õ 0i1A50 , r 1õ HP1')0,141 .6 0 0 N ri HN j 2 AcH AINHe OH y Compound HO
Uomomand 1In-1 NH2 thl 1, NH, According to the reaction route, Compound 345 (ammonium salt) was prepared from Compound 6-8 using the procedure for preparation of Compound 189.

Date Recue/Date Received 2023-07-07 The characteristic data of the Compound 345 was: MS (m/z): 1279.09[M-1]. III
NMR (500 MHz, D20) 8 9.08 (s, 1H), 8.46 (s, 1H), 8.20 (s, 1H), 7.98 (s, 1H), 6.07 (d, J = 5.3 Hz, 1H), 5.86 (s, 1H), 5.83 (d, J =
5.9 Hz, 1H), 4.97 ¨4.94 (m, 1H), 4.76 ¨4.75 (m, 1H), 4.63 (d, J = 4.4 Hz, 1H), 4.54 ¨ 4.50 (m, 3H), 4.46 (t, J = 4.9 Hz, 1H), 4.38 (m, 1H), 4.35 ¨4.33 (m, 2H), 4.29 ¨4.26 (m, 1H), 4.24 ¨
4.20 (m, 2H), 4.17 ¨ 4.14 (m, 1H), 4.03 (s, 3H), 3.53 (dd, Ji = 14.0 Hz, J2 = 8.1 Hz, 1H), 3.47 (s, 3H), 3.29 (m, dd, J1= 14.0 Hz, J2 = 6.1 Hz, 1H), 2.64¨ 2.59 (m, 1H), 2.00(s, 3H); 31P NMR (202 MHz, D20) 8 -0.99 (s,1P), -11.65 (m, 2P), -22.91 (m, 2P).
Example 47 Synthesis of Compound 319 I TaN20.16n0H9420, re.
X u 1 MCI TEA o -.0 NM X -.0 2 N4004, iMe0HH.p, 0 1,C - r.l. 1/40 .t _ .., CPC' DMF, 70PC ..., IX 3 Nre3Nõ re' nOH:1-1. 0, VT - hit.1-110H1C--, 8 Compound 54 Compound 319-1 Compound 319-2 0 it Ph 0 'N' ,eNt1LAHANI AI Compound 139-8 ¨.¨ 920-'.1MC),..0 H280.0 AM) a7n-"-et.-.0A0 ,,, .,___)c-= D....1.-"t2M.-DCM, CPC - LI; p-1 'IX MOH, EA, 49'; e "ime te-V1-10,q ,--- 1.88A DCE, 80 C
Ng frigi Ng 2.17e1SOTin PhMe, 79 C
C,pmpo.ind 5151-1 Oampaund 3194 Compound 319-5 I ,Fh 0 el IXIINIA
NIA, , 141hi pai-IILNH
0 ( I 1 NH AhrON 1401-'4',0"'r^1 N NH = TBDPSa, Pnidezolo TE P8 '....t3I4 13103"'"m0eN N NI-1M _, h6PC . DMF, r.l.
Y-4? rbAc a--4.. bld NS
Ng Mr Corovnurd 3194 Compound 3194 Compouud 319-7 Date Recue/Date Received 2023-07-07 ,k4Dtiji*", NH N,,,ANH, PPlig ' 01..ii . Py TECIPSON N Nhia 3HRTEA, TEA
.........TBDF. N H2 ¨ . win.
11-IF. MP, r.t, THP, HP, 5o,c õ¨,te 16,1 mide¨e .1t1H Adoir-- Lop H2N Cmpfturpl 1194 0 COMPOug'd 319,19 0 00Inp0und 31941 o c.54:11A .1e4)1(NH
iH04-1/4ey Z" N 1 Nt.4 PiallPyjmidazde. ifoN20 <NI NA, ' ISH2 IVO*, TEA, IPCIC .43 TEA 6H pphõ 11..a , EWE, r.t P0(0MIP6 3 0 f--1 'OH anC12. DMF, M.
Ad-IN AP8Pr7 lIFI
COlolpatand 319-12 Comma; 919.13 k 0 0, i :Irillit 73(JILNH
HO-ILO-0 li' N -NH2 b=4.1 CIlic 0723-0 -7-0 L j,04 N ¨74142 6H 6H ,r16H 6H .
TEA ,,,-.^, b1-1 TEA pm' brH
AcHN AcHN
Compound 319-14 rtimpaand 319.15 ,,,,,,,,,44-,N,,, d 1131min ling' 4 6 6 6 : =
ar,0 Nr Ho H..4 - - NEP I'm' d 'ono Ach, DMSCO, r.l. bIN
µc.:44, )1rNYLIP , MN' µ...Ø...tp..t:, 4o-CH
Gpoppound 119 i =, 2 Compound 319 HCf bil Ay,:):
According to the reaction route, Compound 319-7 was prepared from Compound 5-3 using the procedure for preparation of Compound 635-7.
Compound 319-11 was prepared from Compound 319-7 using the procedure for preparation of Compound 6-4.
The characteristic data of the Compound 319-11 was: III NMR (500 MHz, D20)6 9.07 (s, 1H), 5.99 (s, 1H), 4.64 (d, J= 4.5 Hz, 1H), 4.21 (d, J= 10.6 Hz, 1H), 3.96 (d, J= 13.1 Hz, 1H), 3.69 (dd, J= 13.2, 3.4 Hz, 1H), 3.40 (dd, J= 14.2, 8.7 Hz, 1H), 3.27 (dd, J= 14.1, 5.8 Hz, 1H), 1.89 (s, 3H), 1.56¨ 1.53 (m, 1H), 1.44 ¨1.40 (m, 2H).
According to the reaction route, Compound 319 (ammonium salt) was prepared from Compound 319-11 using the procedure for preparation of Compound 139.
The characteristic data of the Compound 319 was: MS (m/z): 1213.05[M-1]-. III
NMR (500 MHz, D20) 8 9.08 (s, 1H), 8.46 (s, 1H), 8.20 (s, 1H), 7.98 (s, 1H), 6.07 (d, J= 5.3 Hz, 1H), 5.86 (s, 1H), 5.83 (d, J= 5.9 Hz, 1H), 4.97 ¨4.94 (m, 1H), 4.76 ¨ 4.75 (m, 1H), 4.63 (d, J= 4.4 Hz, 1H), 4.54¨ 4.50 (m, 3H), 4.46 (t, J=
4.9 Hz, 1H), 4.38 (m, 1H), 4.35 ¨4.33 (m, 2H), 4.29 ¨ 4.26 (m, 1H), 4.24 ¨4.20 (m, 2H), 4.17 ¨ 4.14 (m, 1H), 4.03 (s, 3H), 3.53 (dd, J1= 14.0 Hz, J2 = 8.1 Hz, 1H), 3.47 (s, 3H), 3.29 (m, dd, J1= 14.0 Hz, J2 = 6.1 Hz, 1H), 2.00 (s, 3H), 1.64¨ 1.59 (m, 1H), 1.56¨ 1.54 (m, 2H); 311) NMR (202 MHz, D20) 8 -0.95 (s, 1H), -11.49 (d, J= 10.9 Hz, 1P), -11.58 (d, J= 12.0 Hz, 1P), -22.82 (t, J= 18.2 Hz, 1P).

Date Recue/Date Received 2023-07-07 Example 48 Synthesis of Compound 645 H ""Oed7f ' TeDPSO"'`O'.d. TFIE,T3011;`14P
4f ,, M a NH TIMM', inidtgole NM
4;)bil NT
41-1? P, . 15N NAeli _,..
)0 ma TuF, pm metitour''' Rµ114 rvieNN MeHr4 Compound an-I Compound 6418-1 Compound 1346-2 a1/TEA, TEA HO'A..."0'49NrCI g poos HO-P-0'cl 0.
\YbliAINNH ______________________ . 6H 4, -;,,n.., NH Pf L 'PV IM
idalMile THF, DMF, r 11. " =,...ilN PP , TEA, OW a 1'0 NI-12 PO(ONM)3, 0,C TEAmati).0 'Y
, Nil=
ktoHN
Compound 648-3 Compound 6454 0 ,0=14 No04-0-fir6W0 Hamm{ J144-04-0,14 cHii so ap2.0_91p _0,....Cy.N7X4,130*
6 ,ZnCla,OMF, rL. 6H OH 1 'ft/m.14*(14H w-., 'IF ' (SH c!.)H.

IN-2 ca0 N14, MA 440\m NM2 Lt, TFA
Mls.. Mri MoHN
Compound 643-5 Compound 6415.6 Compound 6454 r,L , 3 p,INNH

pygmy,. inudizolo.N80-1-0-11-0Y1 ciNCNa Zna2, OLEO, r.t.
PR... TEA, Mr, r.t. ,6 6H
TH2 4, MoHN He 6i N yNH
Compowid 6454 Compound 1313-16 NH7 .41.%
1prki'N cl':'=6 H "rNMe`
1--tA 0 3M-114' µNCYAliPt) Compound 4345 Hd 1mi ho,e,r.
NH, According to the above reaction route, Compound 645-3 was prepared from Compound 393-1 using the procedure for preparation of Compound 637-3.
The characteristic data of the Compound 645-3 was: III NMR (400 MHz, DMSO) 8 10.59 (s, 1H), 8.01 (s, 1H), 7.84 (d, J= 4.4 Hz, 1H), 6.46 (s, 2H), 5.74 (d, J= 5.4 Hz, 1H), 5.71 (d, J= 1.4 Hz, 1H), 5.02 (t, J=
5.3 Hz, 1H), 4.33 (t, J= 4.6 Hz, 1H), 3.88 (d, J= 9.1 Hz, 1H), 3.75 -3.65 (m, 1H), 3.55 -3.48 (m, 1H), 3.32 (s, 3H), 2.67 - 2.61 (m, 1H), 2.58 (d, J= 4.5 Hz, 3H), 2.43 (dd, J= 15.2, 8.4 Hz, 1H), 2.19 (dd, J= 15.2, 5.9 Hz, 1H).
According to the reaction route, Compound 645 (ammonium salt) was prepared from Compound 645-3 using the procedure for preparation of Compound 139.
The characteristic data of the Compound 645 was: MS (m/z): 1213.05[M-1]-. III
NMR (500 MHz, D20) 8 9.10 (s, 1H), 8.46 (s, 1H), 8.19 (s, 1H), 7.98 (s, 1H), 6.07 (d, J= 5.5 Hz, 1H), 5.84(d, J= 5.8 Hz, 1H), 5.82 (s, 1H), 4.98 -4.95 (m, 1H), 4.79 (m, 1H), 4.65 (d, J= 4.1 Hz, 1H), 4.54 -4.51 (m, 3H), 4.46 (t, J= 5.0 Hz, 1H), 4.37 -4.33 (m, 2H), 4.29 - 4.26 (m, 2H), 4.23 -4.20 (m 2H), 4.14 -4.12 (m, 1H), 4.03 (s, 3H), Date Recue/Date Received 2023-07-07 3.47 (s, 311), 3.23 (s, 311), 3.06 (s, 311), 2.89 (s, 3H), 2.74 - 2.61 (m, 2H), 2.57 -2.54 (m, 1H); 31P NMR
(202 MHz, D20) 8 -0.88 (s, 111), -11.52 - 11.70 (m, 2P), -22.82 (t, J= 17.9 Hz, 1P).
Example 49 Synthesis of Compound 394 'a i N NH, ?
ONel 2-4. N,N Cr, FIN .,611 ii 0=743-0'.4.1rD)ro N 4112 * T'Otia zilci,,, co I am .1¨J,,,,õri,, DMSO, IA. NM% 3p4tv ......
.Le bH 0 HO
C.2.7,10,` 3821.5 CINNIKKIrd 110'1 DI pound IV
According to the reaction route, Compound 394 (ammonium salt) was prepared from Compound 393-5 using the procedure for preparation of Compound 139, except substituting Compound 139-15 with Compound 110-1.
The characteristic data of the Compound 394 was: MS (m/z): 1160.07[M- l]. 1H
NMR (500 MHz, D20) 8 9.05 (s, 1H), 8.44 (s, 1H), 8.17 (s, 1H), 7.86 (d, J= 8.1 Hz, 1H), 6.04 (d, J= 5.5 Hz, 1H), 5.82 - 5.81 (m, 2H), 5.78 (d, J= 4.8 Hz, 1H), 4.93 (br, 1H), 4.56 (d, J= 4.5 Hz, 1H), 4.51 -4.46 (m, 3H), 4.43 (t, J= 5.0 Hz, 1H), 4.34 - 4.30 (m, 2H), 4.26 - 4.24 (m, 2H), 4.19 (s, 2H), 4.10 - 4.08 (m, 1H), 4.01 (s, 3H), 3.43 (s, 3H), 2.66 (s, 3H), 2.63 - 2.62 (m, 1H), 2.48 - 2.41 (m, 2H); 31P NMR (202 MHz, D20) 8 -0.91 (s, 1H), -11.61 (m, 2P), -22.88 (m, 1P).
Example 50 Synthesis of Compound 421 NI --"=N -t: \ 9 C.
it 9' a rrn NiN2 0 - --7-t-y----" ' , ,, a ON a 'a ' N4k,,, 1)1rk Ohl NH '44 NH Nal)._ P' tiwa o) o µ1 ' ,511,... 0 0 <:,'' I P
a,. 4;171 Ho-P -o -44k0,-, NI) N NHIg JO-TA P
, F
,,,...,..6..."=:?,,...ro +
E .no bH rt. -FE ., LIIH
Fie 1514 NyPIA
MN MI32,ii Cornpoux1 303-2 Compound 4214 Comp:mind 173.3 NFlird 4in r4 y) Ir-j4kr"- " -11-0-41-1-0 NH
1( H IN-r , N HO I
i- - -Nor 2riC12, DM), ri. H2/4 0 _____________ w rIvkil 314He d .." -µ,...õ6,. i=4 Compound 421 HO 6141 1,1 iH1-12 ,.
According to the reaction route, Compound 421 (ammonium salt) was prepared from Compound 393-2 using the procedure for preparation of Compound 173.

Date Recue/Date Received 2023-07-07 The characteristic data of the Compound 421 was: MS (m/z): 1211.10[M- l]. 111 NMR (500 MHz, D20) 8 9.10 (s, 1H), 8.46 (s, 1H), 8.19 (s, 1H), 7.98 (s, 1H), 6.07 (dJ= 5.5 Hz, 1H), 5.84(d, J= 5.8 Hz, 1H), 5.82 (s, 1H) 4.98 ¨4.95 (m, 1H), 4.79 (m, 1H), 4.65 (d, J= 4.1 Hz, 1H), 4.54 ¨ 4.51 (m 3H) 4.46 (t, J= 5.0 Hz, 1H), 4.37 ¨ 4.33 (m, 2H), 4.29 ¨4.26 (m, 2H), 4.23 ¨ 4.20 (m, 2H), 4.14 ¨ 4.12 (m, 1H), 4.03 (s, 3H), 3.47 (s, 3H), 3.06 (s, 3H), 2.89 (s, 3H), 2.74 ¨ 2.61 (m, 2H), 2.57 ¨2.54 (m, 1H), 2.47 (t, J = 20.4 Hz, 2H); 31P
NMR (202 MHz, D20) 8 16.79 (s, 1P), 7.80 (dd, J= 25.4, 6.8 Hz, 1P), -0.88 (s, 1H), 11.70 (m, 1P).
Example 51 Synthesis of Compound 437 apixa, 4c4 :11,1!
t71( N Pra3Py.
C.?Ti-Etj, tipHJ
PPh,, TPA, DNIF 0 JIA2 Mo,N1)0 tjh Nqo, Commind 3413-5 Compound 137-1 1-4-"r4 HO¨P '--0'''¨'"C2rNr341'14 = N

OR OH - r%tle_ N
TEA, Y,01.1 ZreC12, DMSO, rl. HNI _1,14 6 44k," H cie6 H2 Gi Met, JH
'Compound 189-1 2 bH NyNH
Compound 437 NH, According to the reaction route, Compound 437 (ammonium salt) was prepared from Compound 393-5 using the procedure for preparation of Compound 189.
The characteristic data of the Compound 437 was: MS (m/z): 1293.05[M-1]-. 111 NMR (500 MHz, D20) 8 9.10 (s, 1H), 8.46 (s, 1H), 8.19 (s, 1H), 7.98 (s, 1H), 6.07 (d, J= 5.5 Hz, 1H), 5.84(d, J= 5.8 Hz, 1H), 5.82 (s, 1H), 4.98 ¨ 4.95 (m, 1H), 4.79 (m, 1H), 4.65 (d, J= 4.1 Hz, 1H), 4.54 ¨
4.51 (m, 3H), 4.46 (t, J= 5.0 Hz, 1H), 4.37 ¨ 4.33 (m, 2H), 4.29 ¨4.26 (m, 2H), 4.23 ¨ 4.20 (m, 2H), 4.14 ¨ 4.12 (m, 1H), 4.03 (s, 3H), 3.47 (s, 3H), 3.06 (s, 3H), 2.89 (s, 3H), 2.74 ¨ 2.61 (m, 2H), 2.57 ¨2.54 (m, 1H);
31P NMR (202 MHz, D20) 8 -0.99 (s, 1P), -11.65 (m, 2P), -22.91 (m,2P).
Example 52 Synthesis of Compound 415 Date Recue/Date Received 2023-07-07 0 o r, = , ., '= H
H,fro r,...., -a K--- po2 TB5D, irroidazoie ...30600.44,4,,e ,, = ' , ..4 ....,,. ,, , .----.,,i.õ., ...õA ..i,042 ThISCN
il.
and¨A pH lhort''' 'LIM HOr.' =
corrseumdin4 0040gotrer 4154 COOMMInd 4154 _ ni. ( II ,1 6, 4. II .".t 'Mt T1350.-41'¨''r-''' . ' 2 1512 N.:ic..).-. !--,Li 110''µNr ')---; - 4 == rc¨rott _ :õ.õ.........................
._. ,.. H. 0, EDO --:' ' -I F,rµ . -*II
U.
Compouod 4154 _iummound 4154 Compouod 4155 N.
lio .51..0 =,õ,...r,=-= ' r,. 4141141 pv..sf. r.--,)'&,,,IL:
''''.,._..,¨..--'' - f'S' 'W42 af;g111::. :'''''''' f.Ti i ......._. 0 le,-XILIH

--1.
MOHO Oit TEA 6H ,....1 o 'ace. t"
F101140.
Compound 41541 elmripeual 115.7 Cr 0 4'11 ..j.
W-11,17()-1:41:.% ¨:=J'."'N$42 HaDMIF : "lrl f jili Ci141 ........==4p, 0-- V -0 .41.-0 -TEA
6H 6H .
C %sob TE46... =
COMpOwid 41641 - AHIAlo COMpOund 4154 0 n P144 NI , ..., mil, Nti2 14011 ! 41.---=:....1 ...µ: '''''`I0:413-0 10 Ideb."CyNY-11 ... .:::. . ,r,.',,=' 141. ...J. 6 6 6.
t- . - - - 0 j toe 'LLtA: 14-4iSIP - MO W4Hir'' 1'15 liµ4441C.j>41=''e-r:
mce .64 , r'i Ay 111 HCK -bit Compound 135-16. !.4112 Compound 415 Iot According to the reaction route, Compound 415-2 was prepared from Compound 153-6 using the procedure for preparation of Compound 631-2.
Under the nitrogen atmosphere and under stirring, the Compound 415-2 (8.6 g, 15.93 mmol) was dissolved in dichloromethane (100 mL); then TMSCN (10 mL, 79.66 mmol) was added and stannic chloride (5.6 mL, 47.79 mmol) was added dropwise at 0 C. After the temperature was increased to room temperature, the mixture was reacted overnight. Potassium carbonate and potassium fluoride were added to the solution, and then water was added to quench the reaction. A small amount of silica gel was added, stirred, and filtered.
The filtrate was washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, filtered, and purified by column chromatography to obtain 7.2 g of Compound 415-3.
The Compound 415-3 (7.2 g, 13.12 mmol) was dissolved in tetrahydrofuran (20 mL), followed by addition of 10% sodium hydroxide aqueous solution (50 mL). The mixture was heated to reflux overnight.
After the temperature was decreased to room temperature, dilute hydrochloric acid was used for regulating Date Recue/Date Received 2023-07-07 pH to neutralization. Finally, the reaction liquid was purified by C18 column to obtain 3.0 g of Compound 415-4.
The Compound 415-4 (3.0 g, 8.84 mmol) was dissolved in water (10 mL), followed by addition of methylamine aqueous solution (40%, 10 mL), EDCI (3.39 g, 17.68 mmol), and HOBT
(0.24 g, 1.77 mmol), and the mixture was stirred at room temperature. After the reaction was completed, the reaction liquid was purified by C18 column to obtain 2.8 g of Compound 415-5.
The characteristic data of the Compound 415-5 was: 'H NMR (400 MHz, DMSO) 8 10.59 (s, 1H), 8.01 (s, 1H), 7.84 (d, J= 4.4 Hz, 1H), 6.46 (s, 2H), 5.74 (d, J= 5.4 Hz, 1H), 5.71 (d, J= 1.4 Hz, 1H), 5.02 (t, J=
5.3 Hz, 1H), 4.33 (t, J= 4.6 Hz, 1H), 3.88 (d, J= 9.1 Hz, 1H), 3.75 ¨3.65 (m, 1H), 3.55 ¨3.48 (m, 1H), 2.67 ¨2.61 (m, 1H), 2.58 (d, J= 4.5 Hz, 3H), 2.43 (dd, J= 15.2, 8.4 Hz, 1H), 1.92¨
1.89 (m, 2H), 1.68¨ 1.66 (m, 1H).
According to the reaction route, Compound 415 (ammonium salt) was prepared from Compound 415-5 using the procedure for preparation of Compound 139.
The characteristic data of the Compound 415 was: MS (m/z): 1213.06[M-1]. 111 NMR (500 MHz, D20) 8 9.05 (s, 1H), 8.44 (s, 1H), 8.17 (s, 1H), 7.96 (s, 1H), 6.04 (d, J= 5.5 Hz, 1H), 5.82 ¨ 5.81 (m, 2H), 4.93 (br, 1H), 4.56 (d, J= 4.5 Hz, 1H), 4.51 ¨4.46 (m, 3H), 4.43 (t, J= 5.0 Hz, 1H), 4.34 ¨4.30 (m, 2H), 4.26 ¨ 4.24 (m, 2H), 4.19 (s, 2H), 4.10 ¨ 4.08 (m, 1H), 4.01 (s, 3H), 3.43 (s, 3H), 2.66(s, 3H), 2.48 ¨ 2.41 (m, 2H), 1.98 ¨ 1.95 (m, 2H), 1.65¨ 1.62 (m, 1H); 311) NMR (202 MHz, D20) 8 -0.91 (s, 1H), -11.61 (m, 2P), -22.88 (m, 1P).
Example 53 Synthesis of Compound 305 Date Recue/Date Received 2023-07-07 ,ii IA-NH
0:111-x) o '' 0ltill K2 TDOPSO''''''Oall N''''Lli-12. '''''''''Ir TINDPSC".& N NH2 NO
3PPiTEA, TA ........Cr _____________________________ .. e =
( .bH pv, Dal, trC Li t" THP, omr, r.12 ti 'bil Compound 6-2 Cdmpdund n5-1 Compound 3#35-2 0.141j1LNIE1 0, PUC , 0. HoalLar.*141 NP4',Nii, pvs,Ã.,y 1 ,r, Jd, ,48. ,raHice...O.õCf.:4-Pc2 POpr,,.h, LI` C TEA 00N PP'h,, TEN, DI IF ' ar,ti 10}-I

H
Compound 305-3 COrnpodrvJ j05-4 %
H2PO4, TEA _13 0 ijl ri"-(1'NH Mel, plf'NF-1 UP 044 <hi I tir,li,,NH
BA, DMF, a H 41.1H 61-C=1 ....*.3/410.-* ' r't aH all ' +
bn TEA ';, TM
r-r-C1 ir-r1C
Compound ,(36-5 Compound 3064 i=t4 41in ovcir bmt y Ho 2M22, DIASO, ni. . RaN HN
'13 lt,rd11) ITO
14.1r-d'IN'.4. trY:L1 %r21-'11.714 N, 174.1 fiN,r,NH
14Cf im thyl*I
Deendound 13,g-1s NE12 compound 305 INI42 According to the reaction route, Compound 305-2 was prepared from Compound 6-2 using the procedure for preparation of Compound 6-4, except substituting acetyl chloride with n-pentanoyl chloride.
The characteristic data of the Compound 305-2 was: III NMR (400 MHz, DMSO) 8 10.56 (s, 1H), 8.45 (t, J= 5.2 Hz, 1H), 8.04 (s, 1H), 6.47 (s, 2H), 5.82 ¨ 5.79 (m, 2H), 5.15 (t, J= 5.1 Hz, 1H), 4.39 (t, J= 4.3 Hz, 1H), 4.03 ¨ 3.98 (m, 1H), 3.80 - 3.75 (m, 1H), 3.65-3.52 (m, 2H), 3.42-3.38 (m, 1H), 2.63 ¨ 2.57 (m, 1H), 1.92 (t, J= 7.5 Hz, 2H), 1.65 -.1.60(m, 2H), 1.55¨ 1.52(m, 2H), 0.88 (t, J= 7.8 Hz, 3H).
According to the reaction route, Compound 305 (ammonium salt) was prepared from Compound 305-2 using the procedure for preparation of Compound 139.
The characteristic data of the Compound 305 was: MS (m/z): 1238.05[M-1]-. III
NMR (500 MHz, D20) 8 9.06 (s, 1H), 8.40 (s, 1H), 8.04 (s, 1H), 7.91 (s, 1H), 5.99 (d, J= 5.6 Hz, 1H), 5.89 (s, 1H), 5.76 (d, J= 5.6 Hz, 1H), 4.90 ¨ 4.83 (m, 1H), 4.69 (d, J = 4.2 Hz, 1H), 4.53 ¨4.47 (m, 3H), 4.40 ¨ 4.35 (m, 2H), 4.31 (s, 1H), 4.23 ¨4.14 (m, 5H), 4.01 (s, 3H), 3.82¨ 3.77 (m, 1H), 3.44 ¨ 3.40 (m, 1H), 3.36 (s, 3H), 2.64 ¨ 2.60 (m, 1H), 1.90 (t, J= 7.5 Hz, 2H), 1.67 -.1.63 (m, 2H), 1.58 ¨ 1.55 (m, 2H), 0.88 (t, J= 7.8 Hz, 3H); 31P NMR
(202 MHz, D20) 8 -0.94 (s, 1H), -11.52 (m, 2P), -23.01 (m, 1P).
Experimental examples 1. Capping efficiency analysis of mRNA

Date Recue/Date Received 2023-07-07 1.1 Experimental method:
1) A plasmid was linearized and the DNA template was purified.
2) mRNA was synthesized in vitro with 51 types of capping structures of the present invention, or without any cap analogues. CleanCap AG (3'0Me) (Trilink, N-7413) was applied as positive control group, uncapped mRNA was negative control group, and DNAase/RNase-Free water was a blank control group.
The reaction system was shown in Table 1 as follow:
Table 1 Reaction system Component Final Amount concentration DNase/RNase-Free water Up to 20 !LL
ATP Solution (100 mM) 5 mM 1 !LL
CTP Solution (100 mM) 5 mM 1 !LL
GTP Solution (100 mM) 5 mM 1 !LL
UTP Solution (100 mM) 5 mM 1 !LL
Capl Analog (100 mM) 4 mM 0.8 uL
x Transcription buffer lx 2 !LL
DNA template 50 ug/mL 1 lig Murine RNase Inhibitor (40 U/ L) 1 U/uL 0.5 !LL
Inorganic Pyrophosphatase (0.1 U/ L) 0.002 U/uL 0.4 !LL
T7 RNA Polymerase (50 U/ L) 8 U/uL 3.2 uL
Total volume 20 !LL
The system was incubated for 2 to 3 hours at 37 C and digested by TURBO DNase for 15 min. LiC1 was used to precipitate mRNA for at least 30 min, or overnight, mRNA
precipitates were then washed with 75% ethanol. After ethanol was quickly volatilized, mRNA was re-solubilized with RNase-Free water.
3) The transcribed products were purified and the transcription yields were calculated. The test results of some compounds were provided, as shown in Table 2.
Table 2. Final product mass (jig) obtained from the 20 !IL of mRNA
transcription system Date Recue/Date Received 2023-07-07 Example Compound Final product Example Compound Final product Example Compound Final product mass mass mass 1 Compound 139 116 20 Compound 110 106 39 Compound 639 2 Compound 3 108 21 Compound 197 121 40 Compound 323 3 Compound 135 104 22 Compound 195 69 41 Compound 641 4 Compound 141 84 23 Compound 171 105 42 Compound 337 Compound 143 95 24 Compound 173 118 43 Compound 561 108 6 Compound 137 116 25 Compound 189 92 44 Compound 118 7 Compound 635 118 26 Compound 191 123 45 Compound 329 8 Compound 6 103 27 Compound 33 103 46 Compound 345 9 Compound 5 95 28 Compound 151 110 47 Compound 319 Compound 153 65 29 Compound 51 114 48 Compound 645 116 11 Compound 4 78 30 Compound 163 102 49 Compound 394 12 Compound 393 95 31 Compound 631 105 50 Compound 421

13 Compound 58 115 32 Compound 637 88 51 Compound 437

14 Compound 643 121 33 Compound 215 95 52 Compound 415 Compound 633 100 34 Compound 181 114 53 Compound 305 92 16 Compound 309 112 35 Compound 547 103 N-7413 114 17 Compound 311 88 36 Compound 199 95 Negative control 18 Compound 299 105 37 Compound 201 108 Blank 0 19 Compound 219 101 38 Compound 203 96 4) An annealing reaction was performed for the obtained mRNA and probes, and the reaction system was shown in Table 3.
Table 3. Annealing reaction system Component Amount RNase H probe 100 pmol mRNA 100 pmol 10* RNase H reaction buffer 12 IA, DNase/RNase-Free water Up to12011, In a PCR machine, the annealing was performed using the following gradients:
95 C for 5 min; 65 C for 2 min; 55 C for 2 min; 40 C for 2 min; 22 C for 2 min 5) Pre-treatment of magnetic beads were bound with probes.
100 IA, of magnetic beads were placed on a magnetic rack and the preservation solution was removed.
100 IA, of l*BW solution was added, mixed well, and placed on the magnetic rack, and the supernatant was then removed. The washing step was repeated three times. 100 !IL of wash A
buffer was added, mixed well, and placed on the magnetic rack, and the supernatant was then removed. The washing step was repeated three times. 100 IA, of wash B buffer was added, mixed well, and placed on the magnetic rack, and the supernatant Date Recue/Date Received 2023-07-07 was then removed. The washing step was repeated three times. After 120 II, of sample was added, the sample and the magnetic beads solution were incubated for 30 min at room temperature, and they were gently mixed well while incubation.
6) mRNA was spliced to obtain 5' end mRNA single stranded sequence and binding with the probe.
20 IA, of RNase H (5 U/mL) was added, incubated for 3 hours at 37 C, mixed once every half an hour.
100 IA, of l*BW solution was added, mixed well, and placed on the magnetic rack, and then the supernatant was removed. The washing step was repeated three times. Subsequently, 100 IA, of deionized aqueous solution was added, mixed well, and placed on the magnetic rack, and the supernatant was then removed.
The washing step was repeated three times. 100 IA, of 75% methanol at 80 C
was added, and the mixture was incubated at 80 C on a heater plate for 3 min, and placed on the magnetic rack, and the supernatant was then pipetted. The sample was dried using an evaporative centrifuge at room temperature for 45 min to 10 !IL, and then resuspended in 500, of 100 !LM EDTA solution in 1% Me0H for LC-MS analysis.
1.2 Experimental results.
The capping efficiencies of mRNA with different cap analogs were determined by LC-MS, and some compounds of the results were shown in Table 4.
Table 4. Capping efficiencies (%) of mRNA with different cap analogs Capping Capping Capping Example Compound Example Compound Example Compound efficiency efficiency efficiency 1 Compound 139 A 8 Compound 6 A 24 Compound 173 A
2 Compound 3 A 11 Compound 4 A 37 Compound 201 4 Compound 141 A 12 Compound 393 A Negative 0 control Compound 143 A 15 Compound 633 B Blank 0 Note: Ranges of capping efficiency: 100% > A>95%, 95%> B>90%, 90%> C>80%.
From the above table, the compounds of the present invention showed good capping efficiencies, and some had excellent capping efficiencies (>95%).
2. Evaluation on expression efficiency of different capped luciferase mRNAs in HEK293T cells 2.1 Experimental Method:
1) 11NE293 T cells were cultured in a DMEM culture medium with 10% FBS and penicillin/streptomycin at 37 C in 5% CO2.
2) The cultured HEK293T cells were plated into a 96- well plate, with 1.25 *
104 cells per well.
3) After the cells were adherent, a mixture of 0.5 lig of mRNA sample and Polyplus jetMESSENGER , was added to the cells in each well followed by incubation for 6 hours at 37 C in 5% CO2 Date Recue/Date Received 2023-07-07 4) The growth medium was removed to leave the cells to be tested. The cells were washed with PBS.
PBS was removed by centrifugation and 50 111, of lx lysis buffer solution was added to the cells. The cells and all liquids were transferred into a micro centrifuge tube, then centrifuged at 12000 g for 2 min at 4 C.
5) The supernatant was transferred in to a new tube. Luminescence units were measured by using a ONEGloTM Luciferase Assay System kit.
3. All compounds, N-7413, negative control and blank control were tested under the same conditions, and some results of the test were shown in Table 5.
Table 5 Relative luminescence unit (RLU) of capped mRNA
Relative Relative Relative Example Compound luminescence Example Compound luminescence Example Compound luminescence unit unit unit 2 Compound 3 1.72 25 Compound 189 1.46 12 Compound 393 1.74 11 Compound 4 1.65 26 Compound 191 0.93 52 Compound 415 1.53 9 Compound 5 1.26 22 Compound 195 1.64 50 Compound 421 1.27 8 Compound 6 1.84 21 Compound 197 1.73 51 Compound 437 1.36 27 Compound 33 1.35 37 Compound 201 0.59 35 Compound 547 1.43 29 Compound 51 1.33 38 Compound 203 1.65 43 Compound 561 1.22 13 Compound 58 1.48 36 Compound 199 1.10 31 Compound 631 1.48 3 Compound 135 1.07 33 Compound 215 1.09 15 Compound 633 0.88 6 Compound 137 1.41 19 Compound 219 1.75 7 Compound 635 1.34 1 Compound 139 1.65 18 Compound 299 1.67 32 Compound 637 1.28 4 Compound 141 1.46 53 Compound 305 1.53 39 Compound 639 1.58 Compound 143 1.83 16 Compound 309 1.13 41 Compound 641 1.71 Compound 153 1.44 17 Compound 311 1.60 14 Compound 643 1.61 28 Compound 151 1.47 47 Compound 319 1.52 48 Compound 645 1.43 30 Compound 163 1.10 40 Compound 323 1.58 N-7413 1.00 23 Compound 171 1.41 45 Compound 329 1.61 Negative control 24 Compound 173 1.43 42 Compound 337 1.78 Blank 34 Compound 181 1.51 46 Compound 345 1.53 Note: The luminescence unit of N-7413 was normalized as 1, thus relative luminescence unit (RLU) was the ratio of luminescence unit of luciferase expressed by the cells transfected with other capped mRNAs to the luminescence unit of luciferase expressed by the cells transfected with N-7413.
After the capped mRNAs were transfected into 293T cells, the RLU results (6h) were provided in Table 5. It could be seen from the table that mRNAs capped by the compounds of the present invention demonstrated fair expression amount, and some cap structures could provide the mRNA with a higher expression efficiency than N-7413.
In the structures of Compounds 110, 118 and 394 prepared in Examples 20, 44 and 49, B1 and B2 were adenine and uracil, respectively, and therefore the vectors used for these compounds were self-replicating vectors with long-lasting expression, which did not meet the comparison requirement, i.e., the above-Date Recue/Date Received 2023-07-07 mentioned compound should be compared under the same condition. From the Table 2, it could be seen that, when B1 and B2 were adenine and uracil, respectively, the capped mRNA could be transcribed normally, the transcriptional yield was good, and the self-replicating vector could be subsequently employed for long-lasting expression in cells.
3. Stability of the capped mRNA against the mRNA decapping enzymes 3.1 Experimental method:
1) The capped mRNAs were heated at 65 C for 10 min and their secondary structures were unfolded.
2) The concentration of mRNA Deacpping Enzyme was diluted from the original concentration (100 U/uL) to 50 U/uL, 5U/uL, 0.5U/uL in a 10-fold gradient dilution ratio.
3) The capped mRNAs were added to the reaction, and the amount of enzyme in the reaction was 50U, 5U, 0.5U, OU, respectively. The mixture was mixed with a pipette, and was incubated at 37 C for 1 hour.
Component 30u1 Rxn Final Concentration mRNA Decapping Enzyme Reaction Buffer (10X) 3 ;IL 1X
Total RNA up to 32 lig mRNA Decapping Enzyme at various concentrations 1 ;IL
Nuclease-free water to 30 ;IL
4) The RNA was purified using a LiC1 Precipitation method, and then diluted to 500 ng/uL * 20 uL for subsequent cell transfection.
5) The cells were transfected with mRNA, and luciferase expression was detected in the same method as Experiment 2.
3.2 Some experiment results in the test were shown in Figure 1.
Using N-7413 as reference, it can be noted from the Figure 1, that Compound 3 had the same stability as that of N-7413, and Compound 173 at low concentration had the same stability as that of N-7413. However, when the concentration of decapping enzyme was higher, Compound 173 showed a better stability than that of N-7413; Compound 191 showed an excellent stability at different concentrations. Therefore, modification of the triphosphate in the compounds can significantly increase the stability of the capped mRNA against the decapping enzyme.
In Figure 1, the luminescence unit of luciferase expressed by mRNA without decapping enzyme treatment (OU) was 100%, and the percentage of the luminescence unit of luciferase expressed by capped Date Recue/Date Received 2023-07-07 mRNA treated with different concentrations of capping enzyme to the luminescence unit of luciferase expressed by capped mRNA without decapping enzyme treatment was calculated.
The technical features of the above examples can be combined randomly. For the sake of brief description, not all possible combinations of the technical features of the above described examples are described. However, the combination of these technical features should be considered in the scope of this specification, as long as there is no contradiction in the combination of these technical features.
The above described examples only express several examples of the present invention, with more specific and detailed descriptions, but they are not to be construed as a limitation of the scope of the present invention. It should be noted that, for one skilled in the art, a number of modifications and improvements can be made, without departing from the concept of the present invention, which all belong to the protection scope of the present invention. Therefore, the protection scope of present invention shall be subject to the appended claims.

Date Recue/Date Received 2023-07-07

Claims

1. A compound of fonnula IV-A, or a pharmaceutically acceptable salt, + N=\ R9 ya;i ay YILibyc HNNr, N
Y2a Y2b c Y2 =' N \AIR X, C Hy23:a m1 Z1 OR3a R¨NH /

ZiOyB2 bR3b IV-A
wherein, X2 is absent, or X2 is 0, NR4, CONR4, NR4CO, NR4CO2, NR4CONR4, or SO2NR4;
R' is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or benzyl;
X3 iS 0;
R is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C6 cycloalkyl;
Ri is H;
R2 is H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, Rs-substituted CI-Cs alkyl, R5-substituted C2-C8 alkenyl, Rs-substituted C2-C8 alkynyl, phenyl, benzyl, halobenzyl, CN, or N3; when X2 is absent, R2 is N3, or Rs-substituted Ci-C8 alkyl, and R5 is morpholine;
each of R3a and R3b is independently selected from H, C1-C4 alkyl, or CI-Ca haloalkyl;
W is Olt4;

Date Recue/Date Received 2023-07-07 each of Ya, Yb, Yc, and Yd is independently selected from 0, S, CH2, CC12, CF2, or NH;
each of Yla, Ylb, and Yi, is independently selected from 0, or S;
each of V
- 2a, - V 2b, and Y2c is independently selected from OH, or SH;
each of Y3 and Y4, is independently selected from CH2, or 0;
Zi is 0, CH2, S, or NR6, Z2 is CBR7, CO, PO(OH), or PO(SH);
Z3 is 0, NR6, or CHR7;
Z4 is CH2;
each of Bi and B2 is independently selected from natural pyrimidine base, or natural purine base;
R4 is H, Ci-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl;
R5 is C1-C4 alkyl, C2-05 alkenyl, C2-05 alkynyl, CI-Ca haloalkyl, C2-05 haloalkenyl, C2-05 haloalkynyl, 0R7, halogen, CN, pyridine, pyrimidine, or morpholine;
R7 is H, CI-Ca alkyl, C2-C4 alkenyl, or C2-C4 alkynyl;
R6 is H, or CI-Ca alkyl;
R9 is H;
mi is 1, 2, or 3; and n is 1, 2, or 3.

2. The compound, or a pharmaceutically acceptable salt of claim 1, wherein the compound has a structure of formula IV:

Date Reçue/Date Received 2023-07-07 R'\
+ N=A R9 Yla Ylb Ylc 0 õ(X3Y3_ ya y yc 11,_ycr 4 HN N Y2a Y2b 4'2c Wk., _____________________ (0-12)n mi Li bR3a R-NH

Z4,.cOyB2 Fid 6R3b Iv wherein, when X2 is present, X2 is 0, NR4, CONR4, NR4CO, NRaCO2, NRaCONRa, or SO2NRa;

3. The compound, or a pharmaceutically acceptable salt of claim 2, wherein when Ri is H, W is ORa; and R4 is H, or CI-Ca alkyl.

4. The compound, or a pharmaceutically acceptable salt of claim 2, wherein X2 is 0, NRa, CONRa, NR4CO, or NR4CONRa.

5. The compound, or a pharmaceutically acceptable salt of claim 4, wherein the compound has a structure of foimula IV-1:
+
H=a illb illc Ya HN N Y2a Y2b Y2c W (CH2)n ml 'bRia R- NH

Hd dR3b IV-1;
wherein, R' is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or benzyl;

Date Reçue/Date Received 2023-07-07 R is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C6 cycloalkyl;
R2 is H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, Rs-substituted Ci-C8 alkyl, R5-substituted C2-C8 alkenyl, Rs-substituted C2-C8 alkynyl, benzyl, halobenzyl, or CN;
each of R3. and R3b is independently selected from H, CI-Ca alkyl, or C1-C4 haloalkyl;
W is ORa;
each of Y., Yb, Ye, and Ya is independently selected from 0, S, CH2, CC12, CF2, or NH;
each of Y
- la, - Y lb, and )(le is independently selected from 0, or S;
each of Y - 2a, - 2b, and Y2c is independently selected from OH, or SH;
each of Y3 and Y4 is independently selected from CH2, or 0;
Zi is 0, CH2, S, or NR6;
Z2 is CHR7, CO, PO(OH), or PO(SH);
Z3 is 0, NR6, or CHR7;
Z4 is CH2;
each of Bi and B2 is independently selected from natural pyrimidine base, or natural purine base;
R4 is H, CI-Ca alkyl, C2-C4 alkenyl, or C2-C4 alkynyl;
R5 is Ci-Ca alkyl, C2-Cs alkenyl, C2-Cs alkynyl, CI-Ca haloalkyl, C2-05 haloalkenyl, C2-05 haloalkynyl, 0R7, halogen, CN, pyridine, pyrimidine, or morpholine ;
R6 is H, or CI-Ca alkyl;
R7 is H, C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl;

Date Reçue/Date Received 2023-07-07 mi is 1, or 2; and n is 1, 2, or 3.

6. The compound, or a pharmaceutically acceptable salt of claim 4, wherein the compound has a structure of fomiula IV-2:
+ N=\
Yi Y Y
.a lb 111C A4,c(:)....Bi Ya-P-Y -P-Yc -P¨Yd HN ,NrN w __________________ , +2a +2b / +2c =
I111 Z1 Urc3a R- NH
sµZ2 N¨rM Z3 14,n,B2 Hd R3b IV -2;
wherein, R' is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or benzyl, R is H, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C6 cycloalkyl;
R2 iS H, Ci-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, Rs-substituted C1-C8 alkyl, R5-substituted C2-C8 alkenyl, Rs-substituted C2-C8 alkynyl, benzyl, halobenzyl, or CN;
each of R3. and R3b is independently selected from H, CI-Ca alkyl, or Ci-Ca haloalkyl;
W is ORa;
each of Y., Yb, Yc, and Yd is independently selected from 0, S, CH2, CC12, CF2, or NH;
each of v - la, - lb, and Yic is independently selected from 0, or S;
each of V
- 2a, - v 2b, and Y2c is independently selected from OH, or SH;
each of Y3 and Y4 is independently selected from CH2, or 0;

Date Reçue/Date Received 2023-07-07 Zi is 0, OH, S, or NR6;
Z2 is CHR7, CO, PO(OH), or PO(SH);
Z3 is 0, NR6, Or CHR7;
Z4 is CH2;
each of Bi and B2 is independently selected from natural pyrimidine base, or natural purine base;
R4 is H, CI-Ca alkyl, C2-C4 alkenyl, or C2-C4 alkynyl;
R5 is C1-C4 alkyl, C2-05 alkenyl, C2-c 5 alkynyl, CI-Ca haloalkyl, C2-05 haloalkenyl, C2-05 haloalkynyl, 0R7, halogen, CN, pyridine, pyrimidine, or morpholine ;
R6 is H, or Ci-Ca alkyl;
R7 is H, C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl;
mi is 1, or 2; and n is 1, 2, or 3.

7. The compound, or a pharmaceutically acceptable salt of claim 4, wherein the compound has a structure of formula IV-3:
R'\
+N=\
w (CH2)n 0 Via i(V1b)Vic y 0 B
N Nt'"Y3-Ya-ILY -Y, ILYd-- 4 1 HNN , V2a 1(2b V2c 1111 Z1 OR3a R- NH
R sZ2 4¨N

Z4,.ntB2 -HO hR
¨3b IV -3;

Date Reçue/Date Received 2023-07-07 wherein, R' is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or benzyl;
R is H, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C6 cycloalkyl;
R2 is H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, Rs-substituted C1-C8 alkyl, R5-substituted C2-C8 alkenyl, Rs-substituted C2-C8 alkynyl, phenyl, benzyl, halobenzyl, or CN;
each of R3a and R3b is independently selected from H, CI-Ca alkyl, or Ci-Ca haloalkyl;
W is OR4;
each of Ya, Yb, Ye, and Ya is independently selected from 0, S, CH2, CC12, CF2, or NH;
each of Y
- la, - Y lb, and Ylc is independently selected from 0, or S;
each of Y
- 2a, - Y 2b, and Y2c is independently selected from OH, or SH;
each of Y3 and Y4 is independently selected from CH2, or 0;
Zi is 0, CH2, S, or NR6;
Z2 is CHR7, CO, PO(OH), or PO(SH);
Z3 is 0, NR6, or CHR7;
Z4 is CH2;
each of Bi and B2 is independently selected from natural pyrimidine base, or natural purine base;
R4 is H, CI-Ca alkyl, C2-C4 alkenyl, or C2-C4 alkynyl;
R5 is Cl-C4 alkyl, C2-05 alkenyl, C2-05 alkynyl, CI-Ca haloalkyl, C2-05 haloalkenyl, C2-05 haloalkynyl, 0R7, halogen, CN, pyridine, pyrimidine, or morpholine;
R6 is H, or Ci-Ca alkyl;

Date Reçue/Date Received 2023-07-07 R7 is H, C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl;
mi is 1, or 2; and n is 1, 2, or 3.

8. A compound of formula VI-5, or a pharmaceutically acceptable salt, R'\
+ N=\
Yla Y1b Ylc 0 y yc Bi HN õ N Y2a Y2b Y2c W (CH2)n m1 Z1bR3a R-NH
\
R4¨ N z2, Z44, CC1B2 Hd bR3b VI-5;
wherein, R' is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or benzyl;
R is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C6 cycloalkyl;
R2 is H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, Rs-substituted C1-C8 alkyl, Rs-substituted C2-C8 alkenyl, Rs-substituted C2-C8 alkynyl, phenyl, benzyl, halobenzyl, or CN;
each of R3. and R3b is independently selected from H, CI-Ca alkyl, or C1-C4 haloalkyl;
W is ORa;
each of Y., Yb, Yc, and Ya is independently selected from 0, S, CH2, CC12, CF2, or NH;
each of - la, - V lb, and )(le is independently selected from 0, or S;
each of V
- 2a, - V 2b, and Y2c is independently selected from OH, or SH;

Date Reçue/Date Received 2023-07-07 each of Y3 and Ya, is independently selected from CH2, or 0;
Zi is 0, CH2, S, or NR6;
Z2 is CBR7, CO, PO(OH), or PO(SH);
Z3 is 0, NR6, Or CHR7;
Z4 is CH2;
each of Bi and B2 is independently selected from natural pyrimidine base, or natural purine base;
R4 is H, Cl-Ca alkyl, C2-C4 alkenyl, or C2-C4 alkynyl;
R5 is C1-C4 alkyl, C2-05 alkenyl, C2-05 alkynyl, C1-C4 haloalkyl, C2-05 haloalkenyl, C2-05 haloalkynyl, 0R7, halogen, CN, pyridine, pyrimidine, or morpholine;
R6 is H, or CI-Ca alkyl;
R7 is H, C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl;
n is 1, or 2, or 3; and mi is 1, or 2.

9. A compound of formula VI-6, or a pharmaceutically acceptable salt R'\
+ N=\
Yla Ylb Y1 c N y3 ya A y yc yd,y4 Bi HN N
)1(2a )1(2b . NT, w (CH2)n m1 Zi OR3a R¨NH

/

HN

µR2 4.( Hd 6R3b VI-6;

Date Recue/Date Received 2023-07-07 wherein, R' is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or benzyl;
R is H, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C6cycloalkyl;
R2 is H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, Rs-substituted C1-C8 alkyl, R5-substituted C2-C8 alkenyl, Rs-substituted C2-C8 alkynyl, phenyl, benzyl, halobenzyl, or CN;
each of R3a and R3b is independently selected from H, CI-Ca alkyl, or Ci-Ca haloalkyl;
W is OR4;
each of Ya, Yb, Yc, or Ya is independently selected from 0, S, CH2, CC12, CF2, or NH;
each of - la, - V lb, and Ylc is independently selected from 0, or S;
each of V
- 2a, - v 2b, and Y2c is independently selected from OH, or SH;
each of Y3, and Y4 is independently selected from CH2, or 0;
Zi is 0, CH2, S, or NR6;
Z2 is CHR7, CO, PO(OH), or PO(SH);
Z3 is 0, NR6, or CHR7;
Z4 is CH2;
each of Bi and B2 is independently selected from natural pyrimidine base, or natural purine base;
R4 is H, CI-Ca alkyl, C2-C4 alkenyl, or C2-C4 alkynyl;
R5 is Cl-C4 alkyl, C2-05 alkenyl, C2-05 alkynyl, CI-Ca haloalkyl, C2-05 haloalkenyl, C2-05 haloalkynyl, 0R7, halogen, CN, pyridine, pyrimidine, or morpholine ;

Date Reçue/Date Received 2023-07-07 R6 is H, or Cl-C4 alkyl;
R7 is H, Ci-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl;
mi is 1, or 2;
n is 1, 2, or 3.

10. The compound, or a pharmaceutically acceptable salt of any one of claims 4, 8, and 9, wherein R2 is H, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Rs-substituted Ci-C6 alkyl, Rs-substituted C2-C6 alkenyl, Rs-substituted C2-C6 alkynyl, benzyl, halobenzyl, or CN; and R5 is C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, 0R7, halogen, CN, pyridine, pyrimidine, or morpholine;
W is OH, methoxy, or ethoxy;
R' is methyl, ethyl, n-propyl, or isopropyl; and R is H, methyl, ethyl, n-propyl, or isopropyl.

11. The compound, or a pharmaceutically acceptable salt of any one of claims 4, 8, and 9, wherein Zi is 0, CH2, S, or NH;
Z4 is CH2;
each of Bi and B2 is independently selected from natural cytosine base, natural uracil base, natural adenine base, or natural guanine base;
R6 is H, methyl, ethyl, propyl, or isopropyl; and R7 is H, methyl, ethyl, propyl, or isopropyl.

12. The compound, or a pharmaceutically acceptable salt of any one of claims 4, 8, and 9, wherein each of Ya, Yb, Yc, and Yd is 0, or at most one of Ya, Yb, Yc, and Yd is S, CH2, CC12, CF2, or NH;

Date Reçue/Date Received 2023-07-07 each of Yla, Ylb, and Yie, is 0, or at most one of Yla, Ylb, or Y1, is S;
each of V
- 2a, - v 2b, and Ira is OH, or at most one of Y2a, Y2b, or Y2c is SH;
each of Y3 and Ya is independently CH2;
Z2 is CH2, CO, or PO(OH);
Z3 is 0, CH2, or NH; and Z4 is CH2;
R' is CI-Ca alkyl, C2-C4 alkenyl, C2-C4 alkynyl, or benzyl;
R is H, CI-Ca alkyl, C2-C4 alkenyl, C2-C4 alkynyl, or C3-C6 cycloalkyl;
R4 is H, methyl, ethyl, n-propyl, isopropyl, butyl, ethenyl, propenyl, butenyl, ethynyl, propynyl, or butynyl;
R5 is C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, 0R7, halogen, CN, pyridine, pyrimidine, or morpholine; and R7 is H, methyl, ethyl, n-propyl, isopropyl, butyl, ethenyl, propenyl, butenyl, ethynyl, propynyl, or butynyl.

13. The compound, or a pharmaceutically acceptable salt of any one of claims 4, 8, and 9, wherein R' is C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, or benzyl;
R is H, CI-Ca alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl;
Ra is H, methyl, ethyl, n-propyl, isopropyl, butyl, ethenyl, propenyl, butenyl, ethynyl, propynyl, or butynyl;
R5 is C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, 0R7, halogen, CN, pyridine, pyrimidine, or morpholine; and Date Reçue/Date Received 2023-07-07 R7 is H, methyl, ethyl, n-propyl, isopropyl, butyl, ethenyl, propenyl, butenyl, ethynyl, propynyl, or butynyl.

14. The compound, or a pharmaceutically acceptable salt of claim 13, wherein W
is OH, methoxy, or ethoxy;
R' is methyl, ethyl, n-propyl, or isopropyl; and R is H, methyl, ethyl, n-propyl, or isopropyl.

15. The compound, or a pharmaceutically acceptable salt of claim 13, wherein R2 is H, methyl, ethyl, n-propyl, isopropyl, butyl, hexyl, ethenyl, propenyl, butenyl, ethynyl, propynyl, butynyl, phenyl, benzyl, halomethyl, haloethyl, halopropyl, haloisopropyl, halobutyl, halohexyl, haloethenyl, halopropenyl, halobutenyl, haloethynyl, halopropynyl, halobutynyl, halobenzyl, C1-C4 pyridinylalkyl, Ci-C4 pyrimidinylalkyl, Ci-C4 alkoxy-C1-C4 alkyl,or C1-C4 alkylamio-C1-C4 alkyl.

16. The compound, or a stereoisomer, or a solvate thereof of claim 15, wherein R2 is H, methyl, ethyl, n-propyl, isopropyl, butyl, propenyl, butenyl, propynyl, butynyl, difluoromethly, trifluoromethyl, difluoroethyl, trifluoroethyl, benzyl, methoxymethyl, ethoxymethyl, or ethoxyethyl.

17. A compound being selected from any one of the following compounds:
\
N IN
HN , N OH OH OH , = N-.A.,i'l H N OH OH
OH d bm. ,, y HO NY
HO 0õty, H2N Me0 Fe bNie N .-0 , OH d OH

..,c0j....Nr-;1 rb \.....(0.y.N,1 HO' bH N.,.....r NH HO' ' N , NH
'OH y NH2 NH, Compound 3 Compound 4 ,-N=\
Y-k'r 0-17-01-0-17-01V=P
HN ,N OH OH OH ' = N, 14 sr- HO U, ,0 OMe H2N AcHN '15.-(Ale d 01-1 c--=j-F4 H /.1 i \........Nye NH2 Fici bH N,....(NH
HO' bH NH, Date Reçue/Date Received 2023-07-07 Compound 5 Compound 6 N
\ 17 .N= \
0 0 0 .........../ N N.2 oyyN''' HN' -....N OH OH OH 6:c)t)Me r HO
H2N ' 0,..1 612'0H
1,..õ
N--,---( .-...--/ NH2 Hd 81-1 Compound 16 \
0 N 1 HANH. 0 NH
41=\ ID.t..jrN". ""'`O-FLOILO-i(3-0'..--ti"
0 0 0 i 0 HN ....N (SH OH OH ."- N, N
N "'" '3 )-- HO
H7:d OH OH OH
HO q ,ObNe H2N 'P,,-, 0 Hi! , P( )4)4 OMe 0 ..6 d 0 HO' 0 OH NH N
\''..." --(h1=-NH2 - \-....NH
' OH
Hei 'OH
Compound 18 Compound 21 Nxii-NH
I I.1'NH2 0 0 0 ___(Ø.), 0..tõ..:N., .,,,õ 11 II 11 N ' O-P-O-P-O-P-O
HN --0,,, OH OH OH ---1, )* HO 0 d, ,0 We (3 1., N
ti OH
NH, Hd. .6 H
Compound 32 N NIANH
c 1 1.1/,1H2 4:)1.1.' .''''o-A-o4-0-4,-o^Cy HNõ,_õ.,..ry OH OH OH z' =
T HO ct ,obMe HN.õ1õ--N HO OH OH OH 0,0,t)Me 0 0 0) p; 0 H2N K _.44 H2N
45 OH c'''...N.--d OH R-4 / NH
0\

Ild 'OH lid 6H
Compound 33 Compound 34 o o N I'LLNH NIANH
\
0 1 N),NH2 \ N NNH2 +N= \
0 0 0 +1,1= \

0õ-y-4,,,. N-p 0 0 0 0---cy HN \ ,N OH OH OH 4o bme HNõ,_,..-N OH OH OH
r HO T HO 6,..o its, ,0 CR.%

Z 13( d OH N)I---\,..../0,N--- NH H2N
HNO K
d OH rNH
,,.......,N___,N,NH

----/

Compound 35 Compound 36 Date Regue/Date Received 2023-07-07 N N
If ' 1 l'":1 I, :!
\ 111',:r 41-7--- \
0 0 0 + \
0 0 0 o N N NH2 iorsi.'' 130---oN N NH, 0N'' .'"-'0POPOPOt HN.,_,....N OH OH OH
T HO

d A blue r HO ciO=p'\,pbMev,c) r_NH 0 P; N_i HHN2:N N3 OH OH OH
-..----/ \ d OH

\_0_y N=x \c__Oje N....rx IldI OH HO 6H
Compound 37 Compound 38 N NH
\ L, +NJ= \

HN,_,...- N OH OH OH
f HO '-', '0 OMe H2N P( .,,,,,N O
µ0F, d OH \ '-4 ......coiN / NH
N.=--( hid 6H
Compound 39 \ \
-,-N_-_\
o,),,,,,,rN.,, 0 õ,Ø..(1)12,...0-1 __0__OA...0 r-rN
0,y ",:c%.õ 0 i -0 -FL 0 -C)A-0,...-0,.. Nir-.)--;\1,0 .,' HN ,N OH OH OH HN -N OH OH OH
HO 0, 0' 0Me N '''''r NH
'r HO 0, p.' 'we NI-NH
H2N HN d "P,OH d NH2 H2N HN 'P,OH NH2 /o H2N (21 \,....0 \ ._. F.--N \ ._ F.-rN
N ..,T.,),....,,r0 HO' 731-1 ' N , NH HOõ
tiFi ' N , NH
y y Compound 47 Compound 48 ÷
+ N= \

O-Ig-0-0-0-A-C) Ny.).......(NH2 HN,N OH 0H 0H
T HO
0. , d -bnie=--, H2N ¨N d "I., \ OH
C:)... r=14 Ny),.....r0 H'. ' ON -.... NH

Compound 49 \ \
-,N=\ + N= \
O 0 0 0 r"---N
0 0-1-0-OP11-0-i ,),10 Nr"--N N H2 l,,yN,., O ..0,,04-04-04-0....-.-o.o N y),..NH2 /
1 It I
HN _,..N OH OH OH HN N OH OH OH - = N , N
c õ g brvie -'"
Ir HO
d -bro." N 'Ir- HO
H2N 'F3, H2N
' I., (:)'= d OH d OH
µ....to.)... i=N
Ny),,y0 N 0 HO" ' OH N , NH bi-' NyNH
y Compound 51 Compound 52 Date Regue/Date Received 2023-07-07 \
11,L0_0.......---0-0 NcN NH2 1 h HN .,... N OH OH OH

O. , d -bro." r`' H2N L.0,...-- d,...,0,, 'ID, OH
\...,(0\... MI

,,L-../
HO - OH N .,y NH
NH, Compound 53 \
-,N..--\ 0 r=N
CJõ.yN.,, O 0 Fs, 0 F, 0 9, 0 OH OH OH 1 h )--- WC\ 0, p "me ",--- -H2N -...
0"-Nci d OH
µ.,, r=r\I
HO'. ' OH N -,y NH

Compound 55 \
,-N--=-\

1:)r\i''' O 'FLOIL-0-1OLO
HN ,...N OH OH OH
HO 0, (,:i- 'me N "s--"N
H2N 'F', 0 N0"^ d OH
H
c,.5_.. r--N

HO'' ' N ., NH
OH y Compound 58 \ \
-,N=.\
0 0 0 0 f=N -.-N=\ f=N
i, N ,õ 0 , õ,..õ,0 -OA -0 -0A-0 _i_ 0,,,.,0õ. N NH2 Oy4k,i,N.., O ...`,04-0-1J,...04_0NNFiz HN, _.,- N OH OH OH ==IN HN,N OH OH OH ,' , i T HO 0µ broe HO 0' H2N HO-Fi' H2N HO-Fi, d '0 CN d '0 r----N \....,,coy.N;Lro Ny.yo .. . ..1----/
HO' ' OH N .,.'..,,- OH NH HO' -N .,.y NH

Compound 93 Compound 95 ici ( 0 f=" 13 "
1.--." '.o i= o g. o o+N=\"'" ="''-o-iLo-TI-o-ito.'"-0--" H2 HNN OH OH OH ,' , I
1 il r HO 0. tale M....õõM
HN N , .õ-- Ho,FL
r HO OH OH OH d' Ow "' NI M2M
H2N HO-0, OMe d '13 OMe 0 '0 Nyjiyo HO' - Islz,r.NH
CH
HO' ' N ,, NH
NI y NH2 Compound 98 Compound 100 Date Regue/Date Received 2023-07-07 . \
.N..-..\
0 0 0 i.,-=N
0.y.õcr,N,õ 0 &_01L.---0--`=" } 2 4-0-g-o-A-o HN, _-- N ON ON OH I HNõ _....- N OH OH
r HO Os oMe N --''N T HO-OMe N N
H2N Me0 Olk H2N
(5 '0 OMe µ,...õc0)...Nr 11..-NH yNH
HCf HO' ' Compound 110 Compound 111 \
o o 0 /=N 41=\ 0 0 0 0 ,--_N
11 11 11 Ny)...y NH2 osY--Cir 0-P-O-P-O-P-0 NN,),`,NH2 oy-4,..r.."0.--0 Vo 0 a i= cr^-(7)-=
1 , 1 1 li HNõ,_,..N OH OH OH HNN OH OH OH == - I
T HO _ Os broe N
T HOf ) is bmeN
H2N 0 0-k H2N AcHN 0--FL
NMe2 0' Th 0 0)...,,ir\rz0 Ir....NH )1..-NH
,.
HOs HO' ' 0 ' 0 bH
bH
Compound 117 Compound 118 \ \
0 0 0 0 /..-,--N *N=\
0 0 0 /--=N
Or,1\õrN=õ O O.,,,N.y...yNH2 V , HN, _...-,N OH OH OH Q.. I HN N , OH OH SH ,' = ' r HO Os bme ' N ''''''''' 'N HO ps bp.% " N
H2N 0----Põ Hp 07-p, INTh o' `') \.,c0)...Nr------\,3 OMe O "
\cii=r\ro \--o \ rr-NH
sr NH OH 0 Lp ..
HO' ===;,.H 0 Compound 119 Compound 121 \ \
0 0 0 /-----N -1.N=N r--N
ol.,.yN,õ 0 o-Ok 1:0 i 0 N.
_0,.......0õ.
II fi 11 1 0 i 1 I
II
HN HO , _....- N OH OH OH =' ' HN HO N OH OH
bme N
N
r 0 ' r H2N 07 'OMeN N .-FL H2N
OMe d s'0 OMe 0) )1-NH 1,-NH
..L--.[
Ho' - OH OH o Ho - o Compound 122 Compound 125 \
+
\
0 0 0 0 1=N NH
0 N=\ 0 0 0 0 F----N
QrCi'N''' o.õy=stõyN.,, - A_0------0-- Nyki-NH2 ' 1 HN, _...... N OH OH OH ..- -.= N N
HNõ ,.......N OH OH OH -- , N N o r HO 0 OMe r HO _ Os bme H2N -0, H2N Bn0 sir NH
......
,- HOs' ' N NH

OH i ' o Compound 128 Compound 135 \
\ +N-7-- \
0 0 0 0 r.---N
y.,..kir NH2 0 +N=-\
0 0 0 ..,,...õ 11 u 11 0,y,kyN,,. ,.,..õ0_puliuN,,.. NH2 .Y.-Y 5._. OPOPOPO---"s-C1.N
HN, ,..,. N OH OH OH
HN.õõN OH OH OH .' , N .., N T HO
T HO

H2N Bn0 0,p,0;._ bme ---' 'Ome N--'''' N
d o d o (0...,N pr=1:
V
yNH
A---I H0 -i-51.1 N y NH
Hd - 0 bH

Date Regue/Date Received 2023-07-07 Compound 136 Compound 137 \ \

+N=\ 0 0 0 Ci 0 0 0 0 o ..'µO-P-O--0- PP 1 -0..NNH2 1 1 1 im HO
HN HOi N OH OH OH0` d HN,......--N OH 6H OH ,:' ,,.OMe N ,õ iH T ) T 0 ''''' H2N Et0 H2N HO 'P,- , o 0 r="

y NH
..1---/ HO' u HO' -z31.4 NNH
=-:õH 0 NH, Compound 138 Compound 139 \
\ =N=_\ i=-N
0 0 0 -,-N=\
0 0 0 ir= =-=N 0 0 . N,..0,,,,,, H I I 11 N=
o'YN''' ""'`04-0 4-04-0 0 N Me NH, \.,õ , Y--Y
OPOPOPOC) ),( NH' rr i o ,õ...., O O ,", HN N OH OH OH -" , N HN N OH N H ..õ N r HO
0, H. On% ---N
' T HO C7 'r H2N Et0 d o o.y. f \i,--N
r\sr0 OMe Ny).,rp r NH
Hd ' N-, NH
HO , 0 0H y Compound 140 Compound 141 \
\ =N=\ /----N
=N=\ /=N Qycr N,,. 0 0 0 0 o o 0 0 0 NH2 .'"''O-P 0 IP
QYYN 0-A-0.4-04-0'*-CIN',?I' HN, _,-N OH OH OH I
N HNN
T HO OH OH OH d , ' , N
tone/V
T HO 0, P meN H2N HF2C0 H2N 0 -P,- d o d o cly.0 N----r\ro r I.7.7.4i:=1 OMe L .0 r NH NI,O'r HO' O
...- N.:.,N1-1 toll H 1 Compound 142 Compound 143 \
\ = N.--.-A r--N
+N=\ r.---N 0.,AN,,, 0 ,,0-(iFL4-0-0A_0 0 0õcrNõ, 0 01.-Ojdlo-04c:-0 I
HNõ _...- N OH OH
OH OH OH -- , N -_ N T Ho d sr HO /
H2N HF2C0 0,112._ 'Me ""-o' o \eµõcy0 rc).,,,r¨N 0 ...N-r'Nr yNH N
0H o HO'. bH ' N NH
--r Compound 144 Compound 145 \
\ =
0 0 0 r=N
O CP OP? 0 ('"P? 0 c)------11".O-." o A o A o A o^c_1"
(3 Ny;kirNH2 HN, ..õ--N OH OH OH ' ' N , N HN, .....--N OH OH OH , o -,iN NH2 r HO d 'ow T HO' ) d 'ome ----' o, , H2N o ) µ..õ,c5.0Nrer5NrNH 'CyN0 7..-'OH Cr -OH
HO' - N.õ NH
I

Compound 146 Compound 147 Date Regue/Date Received 2023-07-07 \
o, N,., 0 0-0A-4-0-0A_0,.....Ø..
0= N,,, 0 0 NI,NH, 0--FLO-F3'.-0.-(g--0 '' I
OH OH OH r IT
Ho me HN N
T HO OH OH OH ; , , 0, p OmeN N
)--- 0,0O....... ' -----H2N 0 --P,-H2N 0 , 0 (t5...rN,0 r\f,0 Nr T
rNH .
HO N yNH
' bH
' 'H
HO' u "-,-_, 0 Compound 148 Compound 149 \ \
f=N

t-_)+N=AN,0 0 IO., 0 i0:., 0 ii:12,, 0,.......c.". N
0 N o N.
r"--N NH2 YS,.5::VO
1 1 , -- O H , , N
N
, HNN OH OH OH .". N , N y HO
OH H O
r HOR HN N 0, ,C). - Me 0,4 bkle ---/
H2N o , 0 d 0 rd H2N 0 r NH
HO. ' N õ NH
OH i bH O NH, Compound 150 Compound 151 \
\ -,- N=\
0 0 0 f=N
-.- N=\ ff N 0 0 0 0 OY-YN''. O µ04-0-P-04-0 0.t..../..y.N,õe),,,,, il ii 11 N
y)-"I'rNH, HNN OH OH OH
HN --N OH OH OH N T- HO
--,- HOiTh d bNie ---,"
o ,.. , H2N
H2N 0 ' P, -OH ci d o rro yNH 0 ----N
\ kii..... Nr .i.7..\ ..õ,f0 'OH o HO' oH y ' N...., NH

Compound 152 Compound 153 \
\ +N-...,\

+N=\ F.--N
0 0 0 0 OYS'N's O ..""-o4-o-A-o-A-o oN ''' ''''o-A-o-A-o-A-oNyLl NH, _.-- N OH OH OH ; , N , N
HN,,N OH OH OH (ji ,bme NN T HO
r HO
H2N -0Me Y
H2N d 0 OH d 0 OEt 0 /=N
1-----Nr \**"...C.i.....Nõ?....õe .11,.. NH
HO OH Ho'' O
-,_H N , NH
% 0 i NH, Compound 154 Compound 155 \ \+N--.-.--=\ fr--N
/ 0 0 0 i=N 0 0 0 0 +N=\

0 ID . '"P--0-ig-o-A-o^Cr Qr'kyN''. ''''''o-A-o-11-o-A-o^0.'",?'1--NH2 HN, ,,...-N OH OH OH HN OH OH , _....-N OH

r HO d bme --' 0. , H2N - P,-H2N , 0 OEt d o r---N

\C-12-..rNr NH \......c.3_,..N 3 .r HO' ' N , NH
HO ' 0 OH CH

Compound 156 Compound 157 Date Regue/Date Received 2023-07-07 \
\ + N=A /=N
+ N--,.--:-\ f----N IV õ õ,,,,, 9 9 9 0 m NH2 O 0 0 O'y " 0-F -0-P-0 -P-Ci"....-0...'.

,. OH , , HN HO me ,-N OH OH OH -- , N N HN N OH OH
µsr HO ti 0MeN N
----"-s"re Q,Ffi:,_ ' -----HP!

ocF,H d o ooF3 o N
o r="
,(Nr -N0 =Tr-NH
Hd ' OH Hd ., O_H N , NH

Compound 158 Compound 159 \
0,y,,Lr, N,,. 0 .õ 0 0 0 N y.,..õ(,N I-12 0N,õ N 'OPOPOPO
ThO-P-O-P-0-P-0 ?.'11NH2 {
HNN 0H OH OH , , N., N
HN, _....41 QH OH OH T HO 0õ p bime ---' T HO 0, F i bme .--"
H2N -P,-H2N - , 0 c0 r NH 7"
H HO' --_H N., NH
O' .',.. 0 O
uH --1-NH, Compound 160 Compound 161 \
,-N=\ /r=N
OYS0 0 0 ,C:1-19j'-0- -0 - 11IV-0 O N N H2 N,, ,,,, 11 11 11 ' ' 0-1'-O-1'-O-1'-O-ti' NN HH2 HN ,N OH OH
HN _...N OH OH OH N ..... N y HO d 'me --"
sr- HO oMe '-/ 0, /

H,N -. 0 --4\ r%...r\e N 0 ),(NH (i 0 r="
..L-/ Hd ' N ,, NH
HO' ' 0 bH OH y Compound 162 Compound 163 \
\ -,-N=.\ /=N
+ N--,-- \ 0 .--N 0 0 0 4..Øõ11 õ µ , 9 9 9 ,.._ _NF y.,,H,NH, I
."---.Cr ' ' 0-1-0-1,-0-Ff'-0-- 1 HN ,N1 OH OH
OH ; , N --, N
,õ,,N OH OH OH y HO 0 bme --/
T HO 0, 55 bme ".-' H2N 0, /

HN,, , o d o \r ...ff_NH
/N
t \....õ,c0x.N0 Hd ' N NH
Hd % 0 OH i3H y NH, Compound 164 Compound 165 \ \+N=\ F=N
+N---,-- \ .,---N
or,cr,N,,. o i 0 iC1 vo_pp 0 0 0 õ..0 0 N1yõ)rNH, T
HN ..- N OH OH OH 1 =:' '.. N.,,_,N HN,_,....N HO OH OH OH
, ' , d brileN
--' sr HO
H2N 0 OMe 0, /
0, / H,N
o rO o O
(....) \,...,coy. f=N
NO
d 0 -rN
Hd ' 0 OH o \ Hd. ==== N , NH
OH I
NH, Compound 166 Compound 167 Date Regue/Date Received 2023-07-07 \ 41= \
0 0 0 /=N
+ N--.-,\ r.=N 0=

0 a 0 OrYN''' ''''0 A 0 A
(7).,....,õcr,N,õ 0-1-0-1H3+0õ..........0õ...N NH, HN -41 OH OH OH N -õ N
OH OH OH : , N , N Y HO 0 bnie --, r Ho o, , H2N 0,p,C2'..

HA
0 d 0 OBn 0 0 0 /=N
....r-Nr sirNH
. \ H Ho' .1:Ni NNH
O ',...
uH 0 Compound 168 Compound 169 \ \+N.-.:-.-..\ i=N
+N.=\ õ¨N o H, 0 0 0 0 0 A c A 0 A 0'..--0-'NN?.'irNH2 C')N". '''0 P' 0 (13g 113 0 ' O''''--0..
I HN õ N OH OH 6H N
,N OH OH OH HO d 'mile r HO
H2N Me0 O' 'ow "...' H2N 'P
HN ,-0Bn cc o O
=,,c__Oy..N --r'-.Nr \***^^12... H y),,,r,0 r.NH
tm N_ ,.,_T NH
. HO
HO -,bH 0 Compound 170 Compound 171 \ \=N--, r=N
,õ. 9 9 ckt_isy, N,,, o ,,õ,...01,'-HC2-ito.....0 O N 0,ycrA 0 ,, 9 H2 y.,..,,iNH2 0-1-0-i-c .-1-0'.......0'.
Ni),...õ(NH2 HN, _,...N OH OH OH {
, , N ., N HN N
r HO OH OH OH = ".=
ci OMBN
--' r HO H2N Me0 p! O.., H Me0 04,!_ bme '.-,-d o Ol -8 r--_N
N
_,!5...Nr='\r,o e r NH
bH
HO N,NH ' ' bH NH, Compound 172 Compound 173 ->N_¨_, .
, 1 H /..,--N
oN' ''''.0-A-0-P-C2-P-0 N ),e,t NH, 0.y..--.N.,. 0 .,,o-itg12_iT_O-i_c, Ny.iNH2 i HN,N 6H OH OH ="- N, 14 HN, N OH OH OH , , N ,, N T HO 0 time --v r HO d" OMe '"" 0, , H2N Me0 0.,..K.,_ H2N WO 'K-0 \....... col.....
F=N
=1----(0,,r\r/-" N
.......1...õ.kr0 )7...NHoo OH N -1,NH
HO' " 0 bH NH2 Compound 174 Compound 175 \
\ +N=\ r=N
+N.--.\ r.-_N CIYN

o ,i o 0 0 Y
o'--'cr o .'"0.-A-0-A-"". =."'''A24-o-A-.0--6 o----0.**NN?'y NH2 HO brvie HNN OH OH OH ="- N.--.. N
HN, _.--N OH OH OH HO
r d ====
Me0 P H HzN meo 0 p' "õ-'''' 0 ,---N
µ,....coy.,,iyõ,......fo .ir,NH
HO OH
HO'. .1aH N,(NH
= 0 NH, Compound 176 Compound 177 Date Regue/Date Received 2023-07-07 \
\ +N=\
S 0 0 /=N
+N=\ r-----N
0Nõ, 0 0-9F.,-0-,9-c012.;-0,........0 NNH2 (3/'N".O.,,,,,, ,O,õ,0,0 HNõ,,....N OH OH OH , -- N , N
HN, _.--N OH OH OH T HO' Ci bp.i. --' 7- HO d bkie --- o, , o, / His! Me0 H2N Me0 '''''i-i!Xtr-NiC) µ64=0....Nõ?.,,,r0 rNH
' ... N, NH
HO' u -..-...H 0 OH y Compound 178 Compound 179 \
0 s 0 f---.--N
0IS 0 0 11,0,........cy. r..----N
C3'1\i'''O ''''OPOPOPO N ...õ NH, I
,_,--N O O O , , NI N
,.
HN, _....N OH OH OH NH, HN T HO H H H d 'me T HO 0' e '''''' 0, / bM H2N Met) H,N Me0 'P,- d 0 d 0 \***"Ø...N,y)....t.0 NH
Z: HO' -OH ' Ny NH

Compound 180 Compound 181 \
\ -,-N=\
-.-N=\
0 S 0 /=N
O o-A-o-A-O-i1-o 0 N v NH2 041-04_04-0,--(1),NNH2 , i , 1 , , , T 0 HN,,,_, N OH OH OH =", N,. N
HN,N OH OH OH HO d 'Orme -"-=
T HO ci 'ow ---" 0, /
H2N Me0 H2N Me0 ci -Põ,-d o Nr----- \e) N 0 .ir.NH
, Hd ' N., NH
HO' ' 0 bH bH y Compound 182 Compound 183 \ \
.N=A

.., u H 11 11 0 Nr--N NH
,,,, u u H O O`yN'.= =='µ -O¨P¨N¨P¨O¨P¨r yµ7Y1 2 Yksy = 0-P-0 -P-O-P -0'''''''cN )''''f NH2 1 HN, ,N OH OH OH
HN N OH OH OH HO
T HO 0 OMe '"' 0, , Hp Me0 d H2N Me0 /=N
\...õ,cy..0 N 0 ).-NH
HO' -OH Ny ' NH
,.1---/
HO' . 0 bH NH2 Compound 184 Compound 185 \
\ +N..¨..\

+N=\ ,,,,, 11 11 H 1 N 1:3 1 0 0 0 0 Y--Cr = ' 0-P-O-P-N-P-0 N rNH2 O-i-114-04-0 1 1 1 HN,N OH OH OH N, N
HN --N OH OH OH '' ' N -... N T HO d Onne -r- HO d Orme ------ o. , H2N Me0 H2N Me0 d 0 0 0 f=N
NrO \'``-ii, N ,y,O
sir NH
HO
õ.. .:.,H u Hd .--,H N,NH
u "I

Compound 186 Compound 187 Date Regue/Date Received 2023-07-07 HN ,N OH OH OH OH s N, N
dCps:..i...
0. , N2N Me0 HA Me0 'P,- 0 d hy,f0 r NH
HOõL--/,Ho O-H 0 bli Compound 188 Compound 189 -H2N M 0 ' 0. . .
I I
HN õN OH OH OH OH , s N, N
y HO p OMe O. , H2N Me0 'f'-' e 12, (30' µ..Ø..Ny0 \fl--NH
HO'N:.)NH
HO' --bH 0 bH NH2 Compound 190 Compound 191 \ \
0 0 ci2 0 0 /=N
, r HO
4), 0 bMe .r1 0y.õ4.yNH,0,Hu,i0 .,,,,0t0_0te ti0 0%00õ.....O., lziõ ...bmNeyiN,, N NH2 HN,rN
H2N Me0 1-121,1 Me0 'P.-d o coyc `......l...to , =71..-NH bH N-õ,(NH
..\----7 HO' - 0 bH NH2 Compound 192 Compound 193 0,c,y,..
I.5___ OPOPC PO P 0'...--Lr 7 I HN ,-N OH OH OH
= , N , N
y HO H 2N WO ' O. g - 0 Me N2N Me0 0õp,.,..
, 012 d, 0 /:-.--N
Ne,ir-NH
HO
Hd ' N , NH
' bH bH y Compound 194 Compound 195 \
\ +N.= \ f=--=N 1 0-P-O-P-O-P-0 V I HN,,N
0.,1,/,0_' sbMe NI''''N
0õ,, _ H2N Me0 H2N M 0 e 0 d 0 0 r-N n HN
H tIFI y O' s.H 0 O
Compound 196 Compound 197 Date Regue/Date Received 2023-07-07 \
\ i=N
1. N= \
0,,yNõ. O 0213g-01;_o_itc,----0-- r=,,N i 1 0 N,,,(NH 0õy,,,,y+NN,.. CI ,,,µ,õ0_1L01)1-01_0õ...)....
HN ...-N 0 OH
HN ,- N OH OH OH -= , N N -T- HO d bkle )--- HO 0 bMe H2N Me0 0. , H,N Me0 (0 N
'1.--..... e NH
Ho' ' N , NH
' bH y HO' -bH o NH, Compound 198 Compound 199 \ \.N=\ ,¨.N

ll (3 NyLiNH, N,.. ..,,,0 0 C1314 0 0,-..-0.... CP
HN N '' õ O OH OH ,"- N-. N
HN , N O OH OH N, N y HO ' ?We ' -1-- HO - d bMe ''''' H2N Me0 (0 H2N Me0 HN
i,...c.b.y.r=N
N µ 0 yNH
HO' --.....
uH0 -.611 Ni...--NFIN2H
HO' Compound 200 Compound 201 \ \
+N=\ ii=N +N=\
0 0 0 0 0 /=N
0_,g_014-01Lo 0 Oy-4...,,T,N,.. ..¶-.....0___0-1-0-i...,0.---.....-Ø
I
HN õ- N OH OH OH , HN HO - k' b M e ---N 0 OH OH N, N N N
-r- HO 0,4. 0Et '''' --r .
H2N Me0 0 H2N Me0 HN i.,-._N
\''...c. j... e N
)(NH bH NyNH
,,t---/

Compound 202 Compound 203 \
\ -,-N...,--_,, ,--.----N
+N=-\ 1=N 0 0 0 Nõ 0 õ,,,,. 9 9 9 0 0 -11- -tt... -11-N N.2 01'01431'0 0 Ny,ci...,NH2 0-P-O-P-0-13-0'A's_c "
HN --N OH OH OH ' __ ' N +, N HN -- N
y HO OH OH OH -"- NN
.-7- HO 0 , rt_ b Et ' 1-1,14 Me0 H,N Me0 0,4 -0 n - P r =N
NO tp ,. sir-NH
HO" ' N, NH
HO' `-- 0 b H y Compound 204 Compound 205 \
\ -,N=N
0 0 0 /r---N
*N---,--\
0 0 0 r----N OyõscrNõ, ,,,,õ,o_A...1,1 O- _0 Ny,õ,r,,, NH2 11 11 11 ,,,NH2 1 N'F,'-0-F-13-F,'-0.....-- c r HN o N 7 i PH PH H
HN --N OH OH OH ,:.' '", N --., N Ni ...-N HO
O
y HO 0 On-Pr , H2N Me0 0,Ft bi-Pr I-12N Me0 o''P,- 0/ 0 ci/ 0 /=N
sir-NH
, HO" ' N, NH
HO' = 0 bH y OH
NH, Compound 206 Compound 207 Date Regue/Date Received 2023-07-07 " \
-I-N=\
+N-=\ /-=N 0 0 0 0 0 No ______________________________________________________________ H2 0.yek,,,, 50v-01.11-01,ll¨o¨P11-0----c )--N,?-1-1-NH2 ,,õõ,,,____01.0 -P-0 rN",Ic/N
HN --N OH OH OH -- , N, N HN, ___ N
____________________________ i-Pr y HO OH OH OH
)--- HO d b -- o. /
OP/ H2N Me0 H2N Med .- / 0 d 0 0 F--N
Nir-NH
Hd. ' N, NH
Hd ' 0 bH i Compound 208 Compound 209 \
+N-=-\ /-=-N r=-N
,0 ,..0--0:FIL 0 0 FLO
N.y)--N H2 0.y...-..c...r, N,.. O ...,-.õ04(P2 õõ... ,...01o_r HN õ-N OH OH OH I
NJ , N HN,-N
i HO 0 On-Bu HO OH OH OH 6'";bimeN.--"'N
H2N Me0 0,p," H2N Me0 d o d 0 0 r="

µir-NH
= HO'' ' N
, NH
HO' ' 0 OH OH i Compound 210 Compound 211 +N.-=-A r.--N +N=\
.,,,õ, _9_ 9 o o o o 0 r=N NH
r."-,f)--(NH2 0-yN,,, 0 11 4_0õ,....u...N v i 2 HN, _....-N OH OH OH -- , N -__ N HN ..õ..N OH OH OH --, N N
r HO d bme --' )--- HO d OnA.
/ o. , H2N Me0 C:'`''P.- H2N Me0 rN

..L.,.../ HO, HO' ---, 0 uH OH 1 Compound 212 Compound 213 P
0 0 0 r=N .N=.7\ r=N
HN 2 (NN,,. o o-fL012-0:112-0 0 ''`O-A-o-&-o-iLoN"T`rI
HN, ..N OH OH OFI -- ,, N.,. N HyN (sH 6H OH
y HO d me HO , ..iiN N NH2 O' bm. "s"--"
o, , H2N Me0 "P.- H2N Me0 d 0 6 o o C-.75--Nli-r r=N
N D
N?õe s'ir-NH
HO' % OH NyNH
HO' '.- 0 Compound 214 Compound 215 P . \
+1%1.\
Y
0 0 0 o''''0"-P--Ve'....-(___r trN
+N=\

HNõ.õ...,..,N
OH OH OH N
...., n u r HO 0. bMe '-'`.
HN,_...-N OH OH OH = - N, N (...NH
I Me0 'P--O
r HO 0, P. -bm. ' H2N Me0 d 0 V
Hd.
"bH
sirNH
.-L----( N i'NHN2H
HO' u ":õ.H o Compound 216 Compound 217 Date Regue/Date Received 2023-07-07 \ \
+N=\ IN=\
0 0 0 0 f=N

''''''O-P -0-P -0-P-0 .......-C).'() -- sI'r NH2 ''c 0-1,'-O-F-O-Fi'-Oco,r, , , 1 HN , N OH OH OH N
HN -- N OH OH OH -= , N HO
-1--- HO d bme --/ Ni....NH -- Me0 NH Med 'P.,- (:),p(õ,(5_ d Me Y
6 o 1 o / o N rNv ,O
HO" "--_. -- N , NH
OH y HO' ' 0 bH NH2 Compound 218 Compound 219 \
\ +N=\ r----N
+ N..= \ ir=N 0 0 0 0+0-11-0+0O):õ.N HN , N OH OH OH
,rNH2 ()71µ1 '5 ..".'0-P-0-1g-0-1g-Oco)--Ny-yNH2 HN, N OH OH OH - / N , N .y. HO
T HO ) 6 -mile -----H2N meo 0õ.õF[1,_ NT-NH Me0` P, - / o O
\...,õ Irr =ir-NH
HO' - N , NH
O
HO' --H 0 bme y Compound 220 Compound 225 \
\ +N=\ i=N
(:),,,,,cr+ N=\N,,, 0 .,,,,O-Fri,-0 11 -0-0-01Lo r=N 0 .,õ 9 9 NNH2 oy-cyN''= -- o.-1,-o--o-p.--0"-''''(_/..N
I I I \ HN -- N OH OH OH
HN,N OH OH OH ' ' N , N -,-- Ho 0, ri dMe T 0.- 'Om. ----"
H2N Me0 H2N Me0 -Põ,- , 0 6 o o r----N
\'....u....0 N i7..v..õ.fp H
,r HO`' - N , NH
:LT N NH
bn-pr y O
bMe0 NH2 Compound 226 Compound 227 \
\ -,- N --,--- \ F.-A
F--N
+"%,,, 0 11 oovo_oe._0õcor,,,cyNH2 0 0 0 ,õ 11 11 11 N '5_.__ O--O-p-O-p-O
HN p N OH OH OH

HO C5' N , N
HN, õ-- N OH OH OH /, , N
43 r- O. OM e Y
r õp,F:,,p/,_ -Me HO 0 12 ''r H2N
meo H2N Me0 , 0 6 o o /=N

\,....õc0i....N.,,r0 NH
HO" ' N , NH
HO -- 0 -OH y On-Pr NH2 Compound 228 Compound 229 \ \
+ N=\
0 P=NS_ , ,,,,õ0-IfFLo-L4-0,,,.....c rN, . 0 0 0 N,y,õ1õ NH2 1 NH2 Ckycr,N,,. ,,,,-,õ -11 - -11 - - 11 -0 p 0 Fy:/ p O'''...-0-. , I
HN ,- N OH OH OH = ,.._. N, N HN ,N OH OH OH
N , N
-1¨ HO 6' Ome -1¨ HO 6H2 uMe 0õp,,_ H2N Me0 H2N Me0 6 H2c7'6 o /=N

NirNH -OH N ..,),NH
HO
..1--../ ' -- ' bH NH2 Compound 230 Compound 231 Date Regue/Date Received 2023-07-07 \
\ +N=\ /=N
r--N 0 0 0 0 0 O i.,,,s-õ,,,ori_01,..._01_0õ........cANNH2 (:N''' I HN, _..... N 0 OH OH
HN, _.-- N OH OH OH - __ , N N T HO S' b M e r HO d OMe ( H2N Med 0 H2d H2N Me0 ...'"C7y.o.,NrC) \*.'"C___,=19 NI-1,õN 0 ,Tr-NH
, HO' O
".-H HO' 0 b H N NH
y Compound 232 Compound 233 \ \
+ N.-=\
0 0 0 0 r.--N
. ON, . 0 .,,,, 'i? I-12 9 '9 0 Nr---N
N..2 N . 0 P C P 0 P eft...Ø.- rNH2 0.y....( N ,,,50,c, 11 it 11 ,tplzi'OF,'0F,'O'..--cr V 1 HN,.....,,N OH OH OH -- , N ..... N
HN --N 0 OH OH ,- , N, N T HO b Me ""---.
)--- HO S OMe .."--/ 0,,,p/,_ H2N Me0 ( H2N
OMe 0 O
0 ir--N
N
c0yNr.;---\
=ir-NH H N , NH
Hd ' bH y IS. ' 0 Compound 234 Compound 235 \
\ -,-N-=\ /-=N
0 0 H2 0 0 + N=\ i=N

0- 1,,.._C ........Ø.._,..._0_,.....,õ0.õNy....kirNH2 ..õõ, 'fil H2 '? 0 'il o HN, õ.,N OH OH OH -' , N, N
HN.,_..-- N HO
OH OH OH HO d bMe T H2N 0... /
H2N 0, p bme --".
d ' d OMe OMe o 0 F = N
sr NH
,..1--/ O H0' ' N, NH
HO -- 0 b H i H

Compound 236 Compound 237 \ \
-,N =-- \
0.,y(...y N õ. 0 , ..1)1, _212i_oi_o 0 0 0 0............4.,kr , õ0...õ.0_11 _c_F,11 _c2ll H .O,..NrcN NH2 I
HN,N OH OH OH HN õr. N Ho ON Ohl OH (5'. .-,0MeN
r HO o, /
(d. / H2N
H2N OMe 0 OMe 6 o 0 /=N
NO ....f0 \il-NH
HC
H0s. bH ' N.,......,...NH

b H NH2 Compound 238 Compound 239 \
\ -,N=\
+ N..-r--- \ r.:--N 11 0 0 ci 0 oy-""' .."'-o--o-A-c 24-o .,,,.õ.0-11 1212-Lo.i-oõ........\--ON N H2 ' HN,N OH OH OH ,,' , N -, N
HN, _.-- N OH OH OH N T HO d bme r HO 0 bme --- o. /
H2N -P,-H2N 'Põ- OMe 6 0 dMe id \=õ.c..0_y.N\r,L.ro HO' u -...,.H N..),. ,NH
bH

Compound 240 Compound 241 Date Regue/Date Received 2023-07-07 \
\ +N=-A f=N
S 0 +N=\
0 0 ri 0 0*-0 f=N
o 00--.NN?"'"rNH2 N,, õ,,,, ll 11 ,-, 2 11 o'µ`r '5 O 0-P-O-P-C -13-CY****.c r YN'ir 1 1 HN ,N OH OH N, N
HN ....-N OH dH dH ' ' N, N Nr HO ci ome '--' y HO OMe7 H2N 0. , 0õ O. "

H2N `P.,-, 0 OMe OMe 0 r.--N
c0y.,N .r.\\r rNH
Hd '-bH
HO' ' 0 OH NYH

Compound 242 Compound 243 \
f=N
0 S 0 +N=\
S 0 0 i=N
NI
O''' o 'O-P-O-P-O
(-_) N'''SO O P 0 P 0 Ig Ci , N
NNIrNH2 HN i OH 0H OH N , N
"T-- OH OH OH -- , N
o' -0Me "7 -1-- Ho H 0, 55' bMe HO "7 OMe (5 o o, 0 OMe NH
Ny, NH
H
. .-HO' % 0 O' -OH

Compound 244 Compound 245 \
\ +N=A r=N
~N==\
O (1--i (1:11 C-) o-A-o-Vo-Vo"0-" z i 0-P-O-P-O-P-Or , I HN,N
HN _--N OH OH OH ' , , N r OH OH OH Ci" 'bM

0 e'''.N
---r- H053 o, , H2N 0, /6 OmeN HO ---""
-,- c;o ,P 0 OMe OMe ....cOyNrrr-40 rO.r\iirC) 7 str NH
HOs % '-- NH
s ' N
=t---/ OH y HO' % 0 Compound 246 Compound 247 \
\

+N--,---\ r----N 0...,,,/...yNõ,5,0 ..õ.... __õ__FLii_ 2_ N,NH2 to,,,,,,,,,e,,, , ,.Ø...OP-o-Op-o-pS-0,0,r_ N...T.),õT.,\ NH2 N
011100 O ,0 H fi 0 HN,N OH OH OH
OH OH OH = , N, N r HO 0,pp-,_ ome r HO H2N
H2N 0, 0' Ome --' OMe 0 O
OMe d 0 /=N
\...õ.c.Ø...Ne NH
HO' HO' ' N, NH
' iDH III. OH 1 Compound 248 Compound 249 \
\ \
0 0 0 +N---r- \ r---N
H2 NIO ,..,,,,, 2.... my-H_E__,...._c ,ToN,,,,r),I,NH2 O.,õ,IN,,,,O õ.,õ0-OILNH-Ovo-Ovo,,.......OrN N 0 Pi 0 F N
HN ...-N OH OH OH ----, HN --N OH OH OH N, N ---/¨ HO 0_ p OMe y HO

H2N 0, p bme --' -P,- OMe 0' OMe 0 0 r----N
\..,r0...r.\r )r-NH
aH
HO' ' N, NH
''/
HO
' --OH NH2 Compound 250 Compound 251 Date Regue/Date Received 2023-07-07 \ 41=\ /=N
+ N--.-- \ .r--.N 0 14 0000 ii IiI H u 0 NH2 N " ' . O.õ7....o O-P-O-H-N-P-0 -T-NyH"
V I blVie H71:1, /T._ OH OH OH
HN 2._ N OH OH OH ..- , N,... N T HO ci b..--------1¨ HO
0,p_ ----.' H2N
H2N OMe 0 , 0 OMe d 0 /=N
-\r r._3õNe NH
HO
N, NH
' bH
HO' - 0 bH NH2 Compound 252 Compound 253 *N\ -41..-\
.,..\ /=-N ,---.N

..y.--", N ,, . ..,,,c, 1. 0 l 0 i,, 0 0õ......_0õ N ..õ1 .437y NH2 y.-1,1õ.
N '''= --0 ig 0 0, C2 i'' 0 HN, ,õry OH (!:,H OH OH - ', N, N
HN -N OH OH OH OH , , N, N y HO d bme --, NI-- HO O bMe ..---/ 0.20, _ 0õp,,_ H2N
OMe H2N OMe 0 sCi d 0 ... ffN
Nykr NH
HO' ' 0H I .=1---/
',. 0 NH
OH N-'N:
HO
Compound 254 Compound 255 \
\ .\ F=N
-,N=\ /=N 0 0 ci2 ifi) 9 o o,,t.....N 0 ,,,013-0-LCH2...fl...0 rt ........0,0-(_o_j_c -Fi.-(3-1-0".......-0.'N....c)..,i,r 1NH2 y--- -Tr HN, _...N OH OH OH OH

sr HO 0, H2N `P.- OMe 0 , 0 OMe ci r----,N
Ncoi...N1C) j_.,14,17,µõ,r0 .r..NH
N.,..1õNH
HO' "i5H 0 bH

Compound 256 Compound 257 \
\
\o 0 0 0 t--..N 0 0 N NH2 ,5.
0......./....õõrõNõ, 0 ,õµ..õ0-ft-0-51-CC12.1...01.0 NyLiNI-12 ." I I I
I 1 I I i HN , N OH OH OH - '- NN
HN,N OH OH OH OH HO NH OMe r H2N OM
H2N 0, , 04,,p_ , 0 e 0 OMe O _N
NH c5....d.7),),., tp µ4,,c_OyNr\r )r.
N, NH
HO" .13.H bH i NH, Compound 258 Compound 259 \
\
0 0 0 r.--N
+N=\
0 0 0 r.--N O
0 4_04_04NH2 CIC) HN --- N OH OH
HN,N OH OH OH = '=.,_ N.., N --r HO
r HO N-I-1 UMe , H2N
H2N 0,p,_ OMe 0 , 0 OMe ci, o ,=N

\ll,..NH
.. . HO i"DH N,y NH
O H
' 'OH

Compound 260 Compound 261 Date Regue/Date Received 2023-07-07 \ \
0 r----N ill 0 -9F,,- 0 -9P- 0-9P-0,...., (c)_)...Nõ.12,,c, +N=., /=N
+N.==\
oy.--cyN õ..Ø1);_o_Y-04_0,.......,.ce õrty_H N.,, .=
.' y i NH2 HN ...õN OH OH OH i -- __ -- N, N HN, _..õ.N
r H. 0 OH OH N N
d blue --,---r- HO 0...,...Ft oMe ""`"

6 0 OMe OMe 0 F---N
Nr--\r \****0-..N o sir NH , HOõ =:, H N , NH
' -O' ÷
bH OH ---r Compound 262 Compound 263 \ \
*N=\
0 0 0 r=N

ciN''.5 '''µO-P-O-P-0-11L.-----corNNNH2 0..).....-1,,,y, N,,. ....0 ':?1=' 0 9P 0 P C r ,...õ i NH, OH OH I
i -,,. N -... N HN ....N .. O .. OH
'r HO - '<
0 OMe OMe HN
OMe i=N
µ..,,c0)...
(cLc3...r\r N0 Nii-NH HO' u --.,,H N NH

Compound 264 Compound 265 \ \
+N=\ /=N +N-=\ /=-N

N,, C) .,,, 11 it ii NH2 ol,.....--y...,.
.,,n,...õ0- I: I:
ni II
P-O-P-O-P-Or Ni)ly C).''''Y 5 ' 0-P-O-P-O-P-0 Ny7'Llr 1 HN,,N O OH OH ¨ N , N HN,,N OH OH
OH N ..,. N
T HO - 4. oMe "'"'-/ r HO 0, ,0 0Et H2N o H2N
OMe P,-OMe HN
HO,' OH l'hyNH
bH NH2 Compound 266 Compound 267 \ \
+N-=\ /=N

0 0 0 Nõ, ,.,+0+0+0+0,..,(7rN NH2 Oyõ,./,NT .0 '-''O-P-O--A-0-P-0,----c-QrNNH2 Y-Y
HN,,N (sH 6,_, , ... , N, N HN,,N OH OH OH s' ' N, N
T-- HO 0 'on-Pr r HO b" bEt '"r 0õp,,,_ H2N , 0 OMe 6 0 OMe o 1=N

Nµv)ro sir-NH
HO" N ..._.
NH
HO' ' -OH0 OH ( Compound 268 Compound 269 \
Nõ,50 ,..,,,o_TL04_0....ovo ,7...N,T),,i, 0 0 0 õ....., 1 oN''.5 '''''C+O-r-O4H:'OrN ''''' I
õ._rNH2 CLYµr HN,_.õ.N OH OH OH
HN, _...-N OH OH OH -i- HO (.) '0i-Pr r HO

H2N , 0 OMe 0 0 OMe /=N
0....Nr5-Nr Np sir-NH .= .
-.. N ,), NH
HO' 7:=.., 0 HO' oH OH

Compound 270 Compound 271 Date Regue/Date Received 2023-07-07 \
\ +N=\ /=N
:L
HLI.0õ........c... N NH2 "'S-0 1'0-0P-O-OP-O-OP-0 HO bi-pr..."..-c .7.-N.,.?---yN 2 HN ....-N 1 1 1 OH OH OH
OH OH OH -- " N,..., N o -r HO c5" bn-Bu ------' --r- ti --' ,p, _ , H2N
H2N Me 431'"P.,- OMe 0 , 0 O (5 0 F.--N
sir...NH
HOs .. . u HO"' O
-_H N, NH
',...,H 0 i Compound 272 Compound 273 \
-,N=\

0 0 0 /=N

0 .2µ,....0___0_,..._0......._0õ.....,(..),... Ny),,yNH2 HN ...-- P 0 HO N OH OH OH N...,..,,N HN ...-N
-r , ''' 'On-Bu ¨ -r- HO
H2N -P,- H2N
OMe d 0 OMe d 0 (Ply.K1r--NrC) r ....c0i,..N-=1:

sir r-He' .-t,H 0 HO'' ' bH N2...
NH
i Compound 274 Compound 275 +N=\ T=N +N=\

O .2,,,,o:i-,?-0-FL_O-Ovo,./..(cOr N 0 0 ..." 1 NH2 N NH2 '''-o-0.-o-ig-o-A-o-0-"NY'''ri OH OH OH 2- , N-.... N HN --N OH OH OH
-' , N.... N
-r HO y HO d oMe ---"' , H2N O`"P,-- H2N
OMe d 0 OMe O
o /="
.r\r H
HO' bH' 0 Hd ' bH N1.,.. NH

Compound 276 Compound 277 P
+N...õ
0 0 0 r----N +N-=\ /-=-N
CI 11 it 11 0 N
I. .NH2 0-P-O-P-O-P-0c:1)''N'''NH2 04õ..(1\ W.' O o-;to-C1)g-o-CP-o Nr'Cr HN,,N OH OH (SH z ' N, N HN
OH OH OH z , N, N
r HO o' bme '"--"" -r- HO
H d 'ome OMe OMe 6 0 d 0 o r= NI
nrr 0 \ti-NH
.. . ' ' , HO' v 1".:-. HO" N NH 0 H - bH y Compound 278 Compound 279 P 0 \
+N...-\

-t-N=\
0 0 0 /=N
HN ..--N OH OH OH = "
N..., N
11 11 11 0 N NH2 --r HO ci bme QyYN '' 'o-P-0-P-o-P-0 "=?-'1( oõp,,.._ HN bMe HO N OH OH OH ..' , N., N
,,..
1NH OMe 6 0 d1---/.
H2N OMe d 0 y1-1T
\...,c0y..N -r¨Nro HO' N, NH
bH y \ll.-NH

HO'' "'bH

Date Regue/Date Received 2023-07-07 Compound 280 Compound 281 \
\ -,N...-\ r-N
0 0 0 0 0 0 /-,---- N 0 0 Ny),,,rNH, o O g-O- P -0-P-0 1 t 1 I HN ,N OH OH OH , = N -õ N
HN õ HO N OH OH OH
0 d OMe NN 'µ1-- HO d bime '--/
-)--- 0-.. i NH õ
=-õIõNH
OMe re. 'P,- 6 0 I OMe 6 o ....ro,..., e'r yNH
HO' ._ N ,.. NH
HO'..L---/ = 0 OH ----r.

Compound 282 Compound 283 \
\ + N=\ /=-N

+ N=\
0 0 0 /=-N 0 Hõ,50 OH
,õ,,õ..0+0+0-i-0õ
OY''..C=rN''' O ''''O-P-0-1A-0-1"-ON'eLyIN 2 HN, N OH OH OH N --- N
''''r HO OH OH -",, NN
d= OMe r. HO 0, /
0, O'z ''-omeN"-%÷
ho -P,-OMe 0 OMe 6 0 /=N
\......Ø...ry7õfo ..irNH
,L..-.% Ho' HO' = OH0 bme y Compound 284 Compound 289 \
\ + N-=\ r----N
+ N=\
0 0 0 0 i=N H2 0 0 0 o 0-A, -04, -04, -13''''''c N,=.5 ....,04_04_04_0,,,( rNN
HN , N OH OH OH -- = N -õ
N
HN -- N OH OH CSH " , N N '1"- HO d 'ohne --=
(5-0N ....,,HH2 )-- HO d' Ome 0. , N H2 H2N OMe (5 OMe 0, 0 0 F.----N
\..,.,.(0,...r,0 ,ir-NH
,1----( -HO' -brvi et) Hd On-Pr y Compound 290 Compound 291 \
+N=--. \ /----A 0 0 0 0 0 0 0 0.yzyN,, N
0 ,. ,õ 5 =..1 II II II =...,0-n''. y!'yNH2 '''o-A-o-iLo-11-o I HN , N OH OH OH , .,..õ NN
HN õN OH OH OH z = N N -r- HO CH2 uMe 'y HO d bMe 0õFµ,_ 0, / H2N

OMe OMe 6 o \........(0".. /=N
\+..õ(0..., N --r\r )r-NH
HO' '.-- 14;,),,NH
HO' ".- 0 OH
On-Pr Compound 292 Compound 293 \
\ +N=\
0 0 0 + N=\
0 0 0 0 f=N
(3,,,,I,Nr.N,,. O ,µ ii n II
Nõ,f,,,,,,,,=\,õTMH2 (:'N". 0 ''o4-o-&-o-A-o"c )--NNH2 N "0-p-O-p-01-0 I
HN õN y HO OH OH 0)H 0 2 Me N N HN ,N
-r HO OH OH OH - = N,_ N
d onne b ., , H2N
H2N OMe H2C
, 0 OMe 6 0 \......(0,...Nr---\ro \....coyjo = yNH
Hd bH ' Ny, NH
HO
õ1"-^-Compound 294 Compound 295 Date Regue/Date Received 2023-07-07 \ \ fr-..--N

0 0 0 0 \ NH2 0411 -0.-IL04-0--.\- )--NNH2-&-e...Ø. N Nr7Y
HN õN 0 OH OH
HN õ.N OH OH OH , -- N N )-- HO
oMe '`=""
're HO ci 'ohne '-' 0.. / H2N
( H2N --P,- OMe 0 OMe H2d , i=N
\*.r.)...ty0 .trNH , .
..1---/ HO - N., NH
HO' -b1-1 bH y Compound 296 Compound 297 \ \
-,N...--A
0 0 0 /....--N -FN--.-,\
0 N 7 NH2 C)1,--4y 0 0 0O
r----N

oN,',5() '."0-P-0-1g-0-1g-0 N N'' O ""'N'O Fi. 0 l'' 0 F:, 0^--O--",?--ri , , , i HN ,N OH OH OH i N
HN ,N 0 OH OH -, , N., N -r- HO
.)-'- HO bMe *----"

( H2N HN
(:) 0,p,!.. 'mile d OMe 0 H
\.....c3) ...Nir-c) )r-NH
HO' - N -..., NH
HO' .-e)H 0 bH y NH, Compound 298 Compound 299 \
\
-,-N=\ /=N -,-0 0 0 m 0 QYY\j''. Ci P-O-P-0-A-0 0 N, ,,,?..,,,,r,NH2 o'y-jy'"=
="s0- V.04-0 -P-0 NN'rINH2 ,N OH (3H OH i N., HN ,N OH OH OH
HN l y HO (3 OMe y HO = (5 'me ---/N

0 d o H

)(NH
HO' ' N.., NH
HO"' ' OH OH y NH, Compound 300 Compound 301 \ - \
-,-N--.-=\ f--,--N 0 0 0 o-FLO-OiLo-Ov,...0 N.y,),õ1,,NH2 0.yõyN,., 0 ,., N,,,5 ,,co,õ -11- -it- -11-0 p 0 l' 0 0Cr V
i HN ,N OH OH OH i HN ,N OH OH OH z , N..õ N
Nr HO d bMe -1- HO 0" bMe '"--"-, O
0 6 0 /=N
\11.-NH
.-1----=./ HO' H 0'" ' N N H
' OH 'OH y NH, Compound 302 Compound 303 \ \+N.= \ /.----N
+N--,--\ r---N 0 0 0 0 0 0 0 Oy..-/NyN,,. _II_ -11_ _11_ ............0, N y...).õ1õNH2 -o-&-o-p-o 11 11 ----c-OrN".H 2 N 0 F' 0 1:) 0 l' 0 I
I HN , ,,N OH OH OH :", N., N
HN, õ...-N OH OH OH " N -... N T HO o brvie ---' r HO = cf -0Me "---v 0, /

'P-H2N HN 0 , 0 d 0 ....1._i0 rcN
N NH N
, 0 HO'' 0 .:.=_.H N.õ. NH
y Hd ' Compound 304 Compound 305 Date Regue/Date Received 2023-07-07 \ \
+N=\ N + N=N r.-.....-N
o o o r= o o o o,),,õõN,õ .õ,,,õ0-1,._0___0_1_0,.....0,..0 N õ.,,c, SO = 0-P -04-04-0 0 N ..." NH2 HN N OH OH OH
HN .....N OH OH OH i , -= N , N ..,.. I
, N
--,-- HO ci OnneN
c ----1- HO i bMe -----7 0.. , H2N HN

0 (5 0 0 \=,,.i:. ,N0 HO' ' N , NH
HO". -6H 0 bH y Compound 306 Compound 307 \ \
-,N=\ +N=\ i=N
(: NI 0 -OP -0 -OP-0 -Op-c,rNN NH2 0y,yNõ. 0 ..õ,õ0-O-o-Oi 11 t,,LO-F,,-(:)õ,..Ø....0 N
II II II I
HN ..,..N OH 6H OH , '-, N , N HN _..N OH OH OH
N
-1,-- HO 0 OMe -1-- HO 0õp/,_ 0õpi/:?_ Me H2N HN

, 0 re, \fr-NH
HO' - N NH
.-----.( HO' % 0 'OH i Compound 308 Compound 309 \ \
* N=\ i= + N=\
N N,.. 0 µ.,,o-itoi-014.-0 0 r=-N
0õt 1\1 , 9 9 9 0 NNv Ni),...rNH2 'TM/ = 0-P -0-P-0 -P-Or 'e-INH2 Oy-Cr V
HN - N
HN _... N OH OH OH , , N IN
Y HO OH OH OH Cf 'bivie'''iN
--r-- HO 0, /
0 , 6,1 bme H2N HN a' / 0 0 r"---N
\--o...Ny)õfp srNH
HO' ' bH ' N , NH
HO" ' b H NH2 Compound 310 Compound 311 \
\
+ N=-- \ N + N--,--- \ f=N

()N õ, 0 ,.õ.õ,04-0-1,,-04,-0,cor Nrc,,NH2 O "4"04-0-1"-041-0 HN ,,,, N OH OH OH i , , N , N HN - N OH 6H 6H -".

-/- HO
-r HO ci bme r 0, / H2N HN A) H2N HN o 6 o / o -ss--- o - 6 i=N
0- \
\,...õ0\..,rro sir NH ,. .
..-----.(¨
HO' HO' ' N , NH
' 0 'OH - bH i NH, Compound 312 Compound 313 \
\ -,N=.\ t-:--N
r.--N 0 0 0 0 H2 N'Crs N' ''''''.0+0+0+C
C''Y'LrN'== = '''''o4-o-Vo-A-o-"( NN
1 1 i I HN - N OH OH OH
HN _...- N OH OH OH " N , N µ===( HO
, r HO dr bMe ."--'' H2N ¨N 0õp,,,C5_ -olVie H2N HN ,0 0,p/,_ .s stf.-NH
HO' - N , NH
WS. u -1., 0 H bH y Compound 314 Compound 315 Date Regue/Date Received 2023-07-07 \
\
o 0 0 0 1 1 ti it ,.....\...0,,r, N(NH2 O-ky, N/..5-O o-F,-012_013-. 0 N NH2 i HN õ N OH OH OH
HN ,N OH OH OH N N y HO d bme Nr- HO = 0 bme 0, /

H2N ¨N /¨No c_Oy Cr ..."
y NH
HO's - N -õ, NH
HO' O "-H 0 OH y Compound 316 Compound 317 \ - \

0 ni---N NH
+ N=\
0 0 0 r.-_-N

'')--'1"-i¨s. " ..--o-A-o-ILo-iLo 0 N ,õir NH2 Cky4\r",, ...y;kcr 2 HN N OH OH OH
HO -= , 'Me N
HO OH OH OH -",,. N ...õ
N
O OMe Y
Y = d" Y _ H2N N 0õFiõ
,---- / 0 0 NH 0 u r--N

1...,coy...4p Nr-NH
N,,,,y. ,NH
,. .
HO' ' n IbH
OH -Compound 318 Compound 319 \
\ N.=\ i=N
r----N
0.-y\i,,,c,.-0 .õ 9 CI:i 9 0 r\NH2 C. 11,1-0-P--0--1L0c r ",?'yINH2 n''''O-P y I HN , N OH OH OH
HN ,N ) '.1,, OH OH OH ,,, , N N y HO d bme -----"
Y HO 0 bme '-' 0, /

0. / H2N

o HN
0,,,,, \*,,0y.N-r )r-NH
HO'. - N ---, NH
O" H' "
OH0 -OH y Compound 320 Compound 321 \ -, \N=\ /=N
+ N=A
0 0 0 /=N 0 0 0 0 Nyr,ViNH2 C)N'"" O A-o-A-o-A-o 0 ,N OH OH OH
O i N ,N HN ., _, N I I 1 OH OH OH ,/ , r HO Ci Ome HN ---y HO 0 50Me Y
, / H2N HN
H2N ' P,- 0/ 0 d 0 0 \ \
r \ N
H . f---1 f0 HN ...y.5,...r /
\
HO' O --._H N NH
i Compound 322 Compound 323 \ \+Nr---\ /.-,.-N
+ N.,==\ r---N 0 0 0 0 0 OryN,,.,,, II 11 11 N

N ..", NH2 '`O-If' -0-1-0 1- 0/..""Cy'.
oN"" 0-FLO-FLO

I HN, N OH OH OH i , N ,. N
HN, _, N OH OH OH -= , N ,õ. N r HO 0 b me ---' r HO = 0" 'Me Y 0, /

H2N HN o "C) 0 d o \.......icoy. 1=N
0 \ H2N
\k,.õ(%... -r----Nr Ny.)....t.0 Nsir_NH
HO' ,..1 / toH
HO u Compound 324 Compound 325 Date Regue/Date Received 2023-07-07 \ \
r.:=N +N=\ 0 r=N

N .,õ?..õ1õNH2 0N,.. O õ0.,õ,04-04-04_0,.....\,,, ),N,?õõ,(NH2 O1,-- ^-'1;N"' ='''''-o...P,-o _T-o-T-e"--0.-* õ.., i HN, _......N OH OH OH -= , N, N
HN .....N OH OH OH -- , N iN y HO cõ p bme -r- HO 0,4 -me rs-' H2N AcHN
H2N HN , 0 \,....C7,:iõ Nir.jr?õ,1 r0 H2N \'.*T_tNr---\r ,ir-NH
HO"
HO' ' N., NH

-OH bH i Compound 326 Compound 327 \ \+N=-\
+N=A
0 0 0 0 r-"=" (:)...y o 0 0 H2 0 r=N
N .õ?...õri NH2 ol\i''. (3 '''''Co A cH2 I= o A C:0'...--0"NNNH2 N,.. .'"'''0 P 0 111. C
A 0---0.-HN ......N OH OH OH z -N,.... N
HN ......N OH OH OH IN HO d ome --' -r HO 0, P bime o. /
H2N AcHN
H2N AcHN o / 0 6 o \,...,r,yrro \-...Ø....y.,õ,f .irNH
.- HO' bH o HO' -.aH N...yNH
-Compound 328 Compound 329 \ \
-,-N=\ 1=N 0 -,-N-=\
0 /-=-N
NI, 0 ..,,,õ (1-1) ir-il H2 N
0-1-CC124-0-17-0 y\--"TrNH2 Ci"t'S/ ' 0-P-O-P-C -P-0___r NNH2 HN _...N OH OH OH -' , N,.. HN ,N OH OH OH
N..õ. N
.."( HO 0 bMe -r HO 0,P,,,_ 0,,FP, _ 1:DMe N H2N AcHN
H2N AcHN / 0 0 r----N
Ne sir-NH
HO" ' N,.. NH
' ' HO' ' 0 bH - bH i Compound 330 Compound 331 \ \
-,-N..--,-- /--=N
0 0 r, 0......õ/Nrisl,, 0 0 Ci2 0 0 H ckt.--4,,N,.. ..,,,,, 11 II .-.2 N. . '''''''o-A-c -A-o-A-o'O'Nr)"-crN 2. o-Fi,-o---c 1.-o ' I
HN, _,..N OH OH OH N..õ. N
HN .,,,N OH OH OH ,", N,õ. N y HO 0 bMe "---"-'')-- HO d bime ."--' o, , H2N AcHN
0.. / H2N AcHN

6 o o /=N
\=õ,,c)....0 .,,ie sir.NH
. HO' ' NI, NH
HO'. ' bH bH i Compound 332 Compound 333 \ \+N=\ /.-=N
+N=\ r=N S 0 0 , 0 0 0 ci 0 0 0 N1,NH2 c)N '. '''''0+0.-1-C 2'- 11 '_0.----0-NNH2 o N N"' O ,'"'''o-i=-O-A-o-Vo'*-0-' .. i HN ,...N
HN, _.....,N OH OH OH z" N.,.. N Y HO OH ti3H OH d=
,OMeN'''''''N
r HO 0 --0Me "'"-r. 0, , H2N AcHN

H2N AcHN O 0 o / 0 /=N
\..õõc5,...N0 N
- .,õ NH
HO' ' 0 HO' ' .bH bH r Compound 334 Compound 335 Date Regue/Date Received 2023-07-07 \ \+ N=N /=-N
+N---r-N.
S 0 0 r=N 0 S 0 OrAy,N,50 04-0-4-04-0,....c0,70.N.,,?,,,,c,NH2 0-y4N., =''',04-04-0-4-0 I HN õ I
HN b I I 1 H OH OH z , N , N
.õN OH OH OH -r N HO
O
y HO (5 Me -----÷"
0,, H2N AcHN 0, p,...,Ci_ bMe -----y H2N AcHN P,_ Ne) ' 0 r.---N
rNH ,.
HO' . bH
.µ---/ bH HO' - NyNH

-Compound 336 Compound 337 \
\ -,-N_¨_\ /---,--N
) 0 0 S 0 NH2 =\ r=N NrN,,. .õ,, 11 ii u ,,õ....õ.0-11 :=-0-A-c:, j-L.,\...Ø7...NyrN H2 0.y 0 i' N 0 0 l' 0 Iri' 0....Ø..
N
+N Y'sir I HN ,N OH OH OH - , N , N
HN , N OH OH OH -- , HO d bMe Y HO d bMe '"'" 0, /
H2N AcHN 'P,-H2N AcHN 'P,- / 0 c; 0 0 i= N
Nr--r rNH c0y.N,,,?,,,,,e) ,,,,- .
A----( Ho ; NyNH
HO' --bH o OH

C ompound 338 Compound 339 \
\ -,N=\ /=_N
+N----,--\ r=N 0 0 0 C).Y'-µ1,N''' 0 .."0-P 41 4-0-1g-0 O'IyN''= O '''`O-oP-0-olLO4S-0 r r 1 HN ,N OH OH OH -- , N
HN ,N OH OH OH -- , N , N -1-- HO (5 oMe ----".
-sr- HO O bMe '"" 0, , o, / Hiv AcHN
H2N AcHN 07'0- 0 CI
r NH
,.1----( HO' -OH
H0. '-i)H NrNH
' 0 Compound 340 Compound 341 \
\ +N-=\ r=N
+N=-\ r----N 0 ? ? H ? Ni,.LiNH2 0,,y,õcri\jõ),=0 O-FLI-413-01)-0 (:-crN,1 '''.0-r-0-1--N-r-0"--*""c 'r --/
T II HN .õN OH OH OH -- __ , N IN
HN õN _______________________________ y HO Ci OMe Y HO
H2N AcHN
H2N AcHN OH OH OH 0,..pb:-....- --,0Me N ..---'N

t5 0 0 /=N

...,,c.i..0 0 N
r NH
HO
Hd ' N , NH
' --oH o bH y Compound 342 Compound 343 \ \
*F1=\ /=N -.N=\
0000 0 /7=N

1-0-jEO12'-0 0 N 7 NH2 O. N,,. o ..,,,0 l 1 i i HN,,N OH OH OH 6H ' '. N IN
HN ,N OH OH OH -"- N , N r HO
Y HO
H2N AcHN 0):!_ Onne "--"
H21.1 AcHN d,,p,....ci_ bnie d o d o /=N
...,coi..., C,C11..N\r N....õ).õ,..0 .. . ,ii....NH
N -,,c,NH
HO' 6H
HO' ' 0 Compound 344 Compound 345 Date Regue/Date Received 2023-07-07 \ ...4,1=\ O i=14 +N--,--\
", ,",,ovo_vo___.0_0,0.... I=N
N, .,,, 0 0 o 1 0 0 0 Ft2 0 0 B il II
N. .. ' 1.-00 0 l'0 r I
0.ItTH I-I OH OH OH z -= N, N
HN ..-N OH OH OH OH 0 -- .- Nõ N y HO 0 bnie -----' oõ,,_ y HO
, , H2N AcHN
d bme --' H2N AcHN
......(0r\r N
Y.;µf w-NH
HO' O
N.,...i...NH
.1--/ OH
'- 0 Compound 346 Compound 347 \ \
+N--,--\ r...--N 0 0 Ci2 0 0 0 N

o 43,14,- ='''or=tpAc AoAo----Cy y\---1:NH2 'YN''' ',"0 P 0 P 02 o A-o^.-0-- YjrNH2 HN ....N OH OH OH OHN.-.A.,...N
HN,_....-N OH OH OH OH ' , N, N y HO 0 OMe O. , di bme H2N AcHN 0,..."
,-.6 H2N AcHN 0\....coy. f=N
d 0 =ir-NH
HO' N..-yNH
Hd ' OH' .01-1 NH2 Compound 348 Compound 349 \
o 0 0 /-=-N
+N=\ /=N ,,, 0-Vo-A-a-A-o^0"
0 NviNH2 (3.Nõ,c, )0 .,,,, 9 9 C12 9 9 U NNH2 0-P-O-P-C -P-O-P-0 '' I HN ,N OH OH dH = , N ....,. ,N 1 1 1 I
HN ,--N OH OH OH OH N,õõµ.,N y HO 141 oMe )--- Hfr") H2N AcHN 0, , 'P,-H2N AcHN 0, ,d bme d 0 ir----N

)...NH
HO' bEi HO'' .-bH N(NH

Compound 350 Compound 351 \ \.N=-\ r+--N i 0 0 0 +N-=\ /--,---N 0 Ci ..''''..o- A-o- A-o- A-e'c -rr i HN --N Ol H OH OH i ', N --,õõ. =N
y HN --N OH OH 0H = , N, N y HO 0 OMe 0- , HO
H2N AcHN
H2N AcHN
0, NI-I OMe ---"
ci 6 o N D
---)r-NH
Ny, NH
HO' Hd.
..-OH
' ' 0 Compound 352 Compound 353 \ \+N---.-\
0 0 0 r--N
+N=\
0 0 0 0 r.iNk )11F1 o.4y O ''''' OYeWs ,,,, 'Y OPOPOPOcry,1 N"' ' 0-P-O-P-O-P-0 '^i'rNH2 HN ..,..N O OH OH N,,,N
HN --N OH OH OH z ' N, N -,r- HO 0 OMB
s.)--- HO H2N AcHN
( 0õ ;Ci bMe --.
H2N AcHN `P,- 0 µ%=1____ .y.N0 sr-NH
HO' ' N, NH
,. . bil y HO' --- 0 Compound 354 Compound 355 Date Regue/Date Received 2023-07-07 \ \
0 0 0 r.----N 0 0 0 0 N ,,c, NH2 (3,yee721, ,,,. 11 _n_ _11_ N ,,. ,,,,,õ, li 11 11 ,,......c ,i..N,y,),õ,(NH2 -, 0-p-0 p 0 l' 0."*"Ø.. -,-I --- -.-cr sci--- I HN , N 0 OH OH , , N -,_ N
HN ...- N 0 OH OH -- , N -... N )--- HO ' -Me Ni--- HO d bivie "---""

H2N AcHN 2N AcH N
( HN

Ne, \r-NH
N y NH
b H
Hd - 0 b H NH2 Compound 356 Compound 357 \ \ f..-N
r---=N 0 0 0 0 0 0 NNH, o N". .."--ciA 0 " o " 0 ..(..y, Nõ,c,..0 ,.,., 9 5' cl? 0 NH2 .)-----Y
P P "a*--Cr V. I
0-P -0-P-0 -P-Cr---...-c____r V 1 1 1 1 HN , N
HN ,..- N ) '1.'", 0 OH OH -1.- HO
OH OH OH 0' -',0Et N'''''N
i' 'OMe N ''''N "r- HO 0, /
H2N AcHN "P....-H2N AcHN 0 d 0 HN i=N
y0 r-NH
Hd -bH N NH
= 1----/
Hd bH 0 Compound 358 Compound 359 \ \+N-=\ ir=-N
0 0 0 + N=\
0 0 0 i=1\lµ
NH2 ClyN Cr ''''O-P-O-P-0-1g-0 N NH2 , 0 ,,,,.. II II II
o-yN ' , , .'' 'Ir HN N , OH OH OH
HN ,N OH OH OH
HO ',..,Et 0 N .--. N -r- HO
-I- CI U '/
, / H2N AcHN
0 H2N AcHN 0, 0 ir=N
\\r \c,õ0_)_...N.0 NH
Hd ' , NH
,t----/ b H N y Hd - 0 Compound 360 Compound 361 \ \.N=1, 0,y ,,iy õ, 0 õõ....,04_0_,Lo_ILO,,....õ(5,Nr=INH2 0,'",,c--=\N õ, õ,,,,,c,i-01,-0.3,-Nr=c,N NFI2 1 i 1 HN ,N OH OH OH I
-' ' HN , N
-1-- HO OH OH OH -"- N ..,,.
N
0 Oi-Pr HO d b n.-Pr '"-' 0. / H2N AcHN
H2N AcHN 0 6 0 i=N
..r.NH
Ni, NH
HIS' .,bil ,.1---../.
Hd ' 0 Compound 362 Compound 363 \ \+N=-_,\
0 Ni=N NH2 0 0 0 + N.---\ r--N 0 ,,,õ II 11 11 0 0 0 0 0 N NH2 Y4s--r, N'' 0-p-0-p-0 -p-d-**-0.*
c'..---YN''. =."'-o-A-o-A-O4-o 7 , , i I HN ,N OH OH OH ,' , N ..õ
N
HN ...-N OH OH OH ' , N , N HO 0 bn-Bu ''' y HO d Oi-Pr '''' 0- , O. / H2N AcHN -H2N AcHN

cf 0 NH 0 r¨N
\,..Ø...N 0 sir Hd ' N .õ, NH
Hd O

H

Compound 364 Compound 365 Date Regue/Date Received 2023-07-07 \
+N-,--,-- \ ,/,-,-N +N=\ F--N
9 9 9 0 V õ 0 ,õõ 9 9 9 0 N \
' = 0 P 0 P 0 P 0'-'''''. "rir NH2 N NH2 0 N HN .,...N ) 'is, OH OH
OH , N N HO o , , , HN ,,. N OH OH OH N
y HO 0 nne --' 0,,,p/,_ 0, /
H2N AcHN H2N AcHN
0 T=N

yNH
õ1---/, HO O-H 0 Hd . OH N -1,,NH

Compound 366 Compound 367 + N.,..\ r----N +N=\ r---N

N , 9 11 c 11 0 0 Ni,,\,õ1,,NH2 (Dr-4,y ,. . 04_04_04_0,-......cr.
HN .,,N OH OH OH N ,,, N HN, __...
N I
--f--- HO d ontie ''''-' y HO OH OH
OH d= "-,0MeN''''''^r N
H2N AcHN 'P,- H2N AcHN

Ne-irAH
Ho'" OH - N, NH
HO' O
=-- i Compound 368 Compound 369 ) P
-,N=\ /=N
11 O ..o,...,0....1:Y..._044 O
1\1õsr..)7iNH2 0.y.õ.....crN,. 0 .,õ,c)-(1...Ø.1...0-q-ci .. 0 Ny)..NH2 I V
I
HN ...-N HN , OH OH OH z". N N
HO OH OH OH ci' , N N bmeN'''' -7-- HO 0 -0Me =.'""''.
H2N AcHN ' P,- H2N AcHN
d 0 0 \ f=" 0 N
\.'""=Cyy.),õ.õ,f.
yNH
...L.-/
' ,,.
HO' ' i'DH o Hd N bH 1NH

Compound 370 Compound 371 P \
+N=\0 0 0 t-,--,N
4-04-0-i-0,......c1D
0 )...
N,õ?.,,,,rNH2 +N.-- ,-,.\ I=N
\N(1 jL012 O N,\NH2 HN ...- N
y HO OH OH OH -- , N ,.., N
ci bme --HN ,N OH OH OH i NH AcHN 0, , "r HO cfi 0Me ."--/ I r,,, c5 0 /
...f...(:),y., r=N
H2N AcHN

=,c0_)....Ne'...r\r" Hd ' N , NH
-OH y yNH

HO' O
==- H0 Compound 372 Compound 373 Date Regue/Date Received 2023-07-07 \ \
+N=\

0 0 0 r= 0y,.5.0 ., 4 0 C) O Nyõ..Tõ.NH2 .NS ''4-0-P-O-P-0 NrN's=?'''rNH2 ''''D-P-0-0-P '' -HN_N OH 01-1 0H 1 -- , N, N HN, _._..N i t t OH 01-1 OH z , N, N
y H. _________ 0,, p bme y HO ci bme ---7 _,.. "'TAN AcHN NH AcHN 'P,- 6 o i 6 o Hd ..\----[ Hd OH ' N., NH
i-bH NH2 Compound 374 Compound 375 \ \+N=\ T=N
f=N c).........(1, 0 0 0 ."...Ny),,,..,,r o 0 0 0 Nõ. ..µ,õ_Avo_v0,....i.. NN?(NH2 N N," ''''0 A o it2, o ig o 0 y FIN,..--N OH OH 10H N iN
. ..- ..õ, HN.,._..N OH OH OH
y HO
T HO 0 OMe 0... i H2N AcHN
, 0,p,d,_ 'sr.-NH AcHN "P,-r--.--N
Nr N
.
NH Ly HO' : NyNH
HO' 7-. - 0 ,..,F1 OMe Compound 376 Compound 381 \ \ F=N
.14=r\ r=N 0 0 0 0 0 0 0 N y ON,,, O ''''''04-0-P-0-1L0 OY-YN''. .'''o-A-o.--;Lo-iLo HN, N OH OH OH i N, N HNN OH OH OF1 N, iH
y HO ci bme r HO ci bme '¨' 0, , 0, / H2N AcHN

H2N AcHN 'P,- / 0 ../rNH
Hd ..
'' N , NH
ewe on-Pr i Compound 382 Compound 383 \ \
0 0 0 1=N 0 +N--.--- \

O../N,,. 0 .. cOrN NN2 N N 6. ,,µ,,,o -Fi,11 -0 _..1,11... 0 .._111_0O.,.
'''''O-A-04 Nr----y,,LyN
HNN 6,_, 6,, 61_, -- , _______________________ , __ õ N, N HN,,N OH OH OH
' '.,._ N , N
r HO 01-12 OMe ..---/
r HO ci bme ch. /
0, / H2N AcHN -H2N AcHN
6 o O"Põ
o N-1 ---r /=N
NH
OH
H H0' ' N,y. NH
d' '".;., 0 un-Pr NH2 Compound 384 Compound 385 \ \+N-...-\ /=N
+N.----\ r--N 0 0 0 N'''S =''''o-A-o-&-o-A-o"c r"1-0.."0..N
I 1 I 1 HN___.N OH OH OH z ,,. N, N
HN, _....-N OH OH OH - , N.,. N y HO
r HO C1-12 oMe ----"
H2N AcHN
H02C.)io_ 0 Me '"' H2N AcHN 0,r(,_ d 0 r---N
\,.....õ0,_,------\,0 N
U'''' \r-NH
Hd ' N, NH
,L1¨

Hd -0H 0 -0H y Compound 386 Compound 387 Date Regue/Date Received 2023-07-07 \ \+N=-\ r.-=N
+N..-:.--,\
0 0 0 F.---N 0 0 0 0 Qy--.Yis 0 ''''04-0-P-0-P-OrN NH2 µ?'ir õ...õ..0 -A - 0 -vo -A -07.,õ.c...or N N H2 I I I
i HN, ..,...-N 0 OH OH
HN -- N OH OH 0H -," ' N -õ N r HO bMe y HO H2N AcHN
0, p OMe ----7 H2N AcHN " P,..,, 0 H2d - Ne) i=N

\-----r -"Y'L
HO''' H NI ,.. NH
b HO' - 0 b H NH2 Compound 388 Compound 389 \
\
N 0 0 0 0 ,F=N
-F -=-\ [-=-N c:)....õ.( N N y.,, 0 ..õ.õ. ii ti II H2 0 0 0 0 ,,,,,, 1 1: c, -P-O-P-O-P-0 : iii ,.......tr 7 OH OH OH d-" '-bime N ...,,N
HN, _....- N ... ,,, N ,..õ,,,N y HO 0õp/õ._ r HO S OMe H2N AcHN H2N

o N7r0 )r-NH
bH
H H0. ' N ..õ NH
ObH ---r-' Compound 390 Compound 391 \
\ +N==\ F=N
+ N=.\
0 0 0 F--N fjy.-µ1,N, O
...,....04L0.1L0:110......õ0.....

...``,0_pP_0-"ty 7 NH2 1 1 1 1 h HN ...- N OH OH OH 1 HNN OH OH OH d,' --ome N ...õN
r HO
0, , y HO
0, /
d --onne"-,-" H2N
0 N ..,- 'P,-H2N `P.,- 0 N/c,NO
\\Cy.) Nr-'--\\rO

).1.-NH
H 0' H
HO' - N
...., NH
-.:-., 0 bH --r-t.J

Compound 392 Compound 393 \
\ +N--.:.-\ F=N
-.14-=\
0 0 0 0 0 r=N Qy--yN.,, (11 0 (1:F; 0 17A1 0 7 , O---/"." ..'o-iLo-Vo-A-o^0--"....r N H2 HN N OH OH OH : , ' HN,,N OH OH OH " " IN sr HO d bMeNN
T HO 0, 0i 0 Me N 0 N

0 N7 ''''''' 0 O H
H

\=õc.,0_.....N--r\r sir-NH
HO' bH 0 HO' -bH NNH
' Compound 394 Compound 395 \
\ +N.¨...\
+N=.\
0 0 0 0 r---N OrcrN.õ CI 1L0i_041 Nr-0....õ õ...",,,r N.,5 ,,,,,õ,0_A_04_04_0,-.....Ø...N
, h HNN OH OH OH --HN, OH OH OH ' = 1 r HO
O. , r HO
O. /
d 'ome"." H2N -Põ-H2N ' P, - 0 N"--'"------ 0 0 N."--Ý.--=.N
I NOe .7rNH
HO' - N ..õ
NH
HO' ' 0 bH --r--OH

Compound 396 Compound 397 Date Regue/Date Received 2023-07-07 \
\ 11=N=\
/=N
../.-=N ci.ykyN,,, ,,,,õ01_0i-0-9A-0,,,,....u...
N)/.).,,,,,õ(NH, 0 y.r,N.,50..õõo_Cij:_o_ito_ov H e.....o...0 NNH, HN ..,..N OH OH OH

, ,Cfo N --N OH OH OHIN
-r- HO
y HO \ 0, /ci' brvie- H2N QP,-`. H2N
0....N...--,-. '13.- d y H

...Nr-I'INej V
NH
HO -, N, NH
HO o --,,H 0 uH y Compound 398 Compound 399 \
\ /=N
,N, =A
N
0õ 0 ,,,,,,,OA91g-0-9A

-,-N /=N ,,.... j.,.. N\irri N H2 C)n)/ " . " 'o-A-o-ig-o-A-o'-0- NH2 -- -,0meNõN HN-rõ.N HO OH OH OH ti, c)MeN*---IN
OH OH OH
H,N
O N, 0, /
'1:), -ci 0 N'-÷- 0' H
/=-N
H c_y0 )r0 N
yNH OH NyNH
HO ' 0 bH NH2 Compound 400 Compound 401 \ \
r.--=\ /=N

0...crõ,, 50 ,,,,,,0-FC,),11-049)5-0....9v.0,.....5.) Nr-IN NH2 0,y--- .NcrN,õ 4 ..Ø--Ø... NNH, OH OH OH -"- N N HN, _.....N OH OH
r HO 0, /0 OMe I'"I,"'"" r HO
brµileN'''''' H2N 'P,- H2N
O N0, 'P, 0 N'I'' d (3 d OH
H H
\....,c5....r'Nr yNH yNH
HOI ' 0 HO ' 0 OH
OH
Compound 402 Compound 403 \ \
0-Nõ,c,, 9 9 9 ........õ( ^,/,... N-1,;31õ,r0 01\ ',, , 9 9 0 Ni=N
NH, -PO-H THC)-PO-H 1---1 nr NH HN N -PO-H 11-H
III
T-- HO 0, g o- y HO
ci wl --omeNIN

0 N0õ. `P, 0, OH NH2 H2N
O W.-I"' H l \,..õ. co...,N7),,ro ,.
HO b ' N, NH HO OH NyNH
H y N

Compound 404 Compound 405 \
0 0 0 0 /=N Oyõ..y.õ 0 t0H11_01.0,---0,..
n.,,,,0_A_04_0_111_0.,.....0,,,NrN H2 HN N HO O õ..H OH OH .." , Me N N
OH OH OH -: , I \ I IN -,r-- Ci o y Hol-\ 0, 0- bivie-'-'," H2N 0, /
'P,-0"N,,,-,,,,. 'P,- 0 N"--"'"' 0 d L.
I \ .,r (3.= r=1\s N) j,ej yNH

HO,.1---/
- N, NH
OH y HO i... 0 uH NH, Compound 406 Compound 407 Date Regue/Date Received 2023-07-07 \
\ +1\1====Th 0 0 0 /=-=N
+ N=. \ f=NO 0 0N,5,,0,2,,õõ,L(Jo-Lyõ...õ (a)...NNH2 N"'n''''''o-A-o-ig-o-Vo Ny),õTAH2 HN ....-N OH OH OH 1 HN .....N
y Hag \ OH OH OH
0., 0"--0Me N'NI
y HO \
0, /
ci 'time N N H2N
0.'"N..."..õ_0õ, 0^N..---õ,..
d 1 Ni=N
I-, yNH
HO' - N ., NH
H0 - 0 OH y oH NH2 Compound 408 Compound 409 \
\ +.1\1=\ 0 r---..-.N
+ = \ 1\1 0 0 0 0 r=N N
o---r".p.'''o-A-o-A-o-A-o I I I ./.....Ø..N NH2 ." ID
HN ,,,..N OH OH OH z , N IN
HN .4! OH OH OH " y HO 6' 'me .-''' -r- HO \ 0, 0' -bMe 1\1 .N''. H2N
Ce-**N---..õ..,.Øõ,, 0 d 1,0 I , \7),10 yNH HO,1-----/
- N .õ NH
-OH yHO' -.,._ 0 uH NH2 Compound 410 Compound 411 \
\ -,-N---õ, 0 r="
+ N=\
0 0 0 r= N 0 0 0 0,yµsyN.., 0 .,,,, _pH _0 _p,t_ 0 _p,, _0..........c.),,, Ny)..,,,, õrNH2 NH
O
HNN HO OH OH OH Oz"
'.,,()me NN
HN, .....-N OH OH OH
HO 0, /cf" time N,IN y r H2N 0 0,N,====-=,õ_,ON, 0----. I
Ct N y _tN-7)õf0 /
NH
HO' - 0H N., NH
y Ho' - 0 'OH NH2 Compound 412 Compound 413 \
\ +N=1,, 0 0 0 0 pr--N

..',, 11 H 11 ,y---(,y N = õ5 0 r=IN ).Ø,.0 _Ci,?_ 0 (1-_0 C)IY'''' .. I ..
O-Fi"-o-F .. C) i' O-o-F-HN,N OH OH H
OH r HO
OH OH
y HO No 6 --olvie"--," H2N o H2N ---õr0 'P.

\,......r0., r=-=--N
N
,., ..., ..trNH HO,L--1 u -,_ N ., NH
0 u H -, H0H ---i, Compound 414 Compound 415 \
\ -,N=\
0 0 0 0 r=N + N----=\

N.5...R,µ,.., II II II N=õ (3 ..,,,õ 11 il u Y-' OPOPOPON),) oY-/ 0-P-O-P-O-P-01\if NH2 HN - N OH OH OH
HN, _õ-N OH OH OH ' = I ...i". HO
. /
O oMersiN
r HO
0, /
CI bMe 11N H2N 0 0,p,_ H2N .õ,f0 ' P, -d 0 HN,,,,0.- 0 HN õ, \'...,r0 Nr---\ro yNH .
HO, - N .õ
NH
HO' ' OH0 OH y Compound 416 Compound 417 Date Regue/Date Received 2023-07-07 \
\
+N=A +N=\
0 N 0 0 im---N
0 0 0 0 1=N

olõ,,4õ,,,72,N,õ , o-p-c -p-o-p-o.03 1,:),..cr N .,3, ^2õ.1,õ0_Vo_Ar_o_v.0õ-.....Ø..,Ny,,y7 NH2 1 I
N ..õ 0 HO .N 1 HN,N
T HO OH OH OH
H OH OH OH
0, P -me ' y \
. , ci 'bivieNN
H2N o H2N ...yo ' P,-0 /N¨ d p-=-.-N
HN,,,-,(0.2-- \+,,,ty...0 Nr'--Nr \0...., NN?õ,õõr0 NH
Hd ' N, NH
HO' -,-., n OH y uH - NH2 Compound 418 Compound 419 \
\ -,N=\ /-='N
+N=-\ f------N 9 H
0.y...yN,,. 0 .õ,,õ0 A 0 it,!, c2 111 0 O
N,y,....,rNFI2 (:)..........-(k....r,N... CI ,.µ,...õ0-11:1-Fic2-(iLoHS:Lo O
kly.),,,TAH2 i /
I .....N
OH O HN H OH i = N, N -r- HO OH OH OH
ciz ',,c)me N.-1=/N
y HO = 0 -0Me '11 N¨ 0 H2N 0 N¨ d o , 0 / 0 f=N
r 1 \.1,7>,..N1-. - N, NH
OH
Hd HO' uH NH2 Compound 420 Compound 421 \ \+N=\ N
/1= k +N=, /=N 0 a 0 0 gy,..crNõ. 0 õ
k 0 ,..õ, 9 9 H2 9 (:).YY ' 0-P-O-P-C -P-0NNH2 HN,_,--N
HN, ,N OH OH OH i '-,, O N,, N r HO OH OH OH
6" 'bMeNN
y HO 0 Me 111 0, /
0, / H2N 0 "P"-H2N 0 'P,' N¨ d o / 0 N N¨ 0 )1...NH
HO" ' OH N, NH
' -Hd ' OH -o NH2 Compound 422 Compound 423 \ \
-, +N=-\ T=N 0 0 0 W. r, o '-'.2 11 ..,õ0.fo_fc 0yNõ, 0 .õ,õõ0. i....12i1....01...0 9 O bMe N OH OH OH -"- N, N
HN HO N OH OH OH /
O N, N T HO
0 bme ----' T
.
H2N 0 H2N o N¨ d N¨ O / /=N
/
NO ..,,r0 \i ,tr/-NH
Hd ' OH N, NH
d u H1 1"---H 0 Compound 424 Compound 425 \ \+N--,--.\ r---N
+N-----,\ /=--N
0 j_o_fi,l-CC12.1?_0 O N NH2 o1Y41y1s, N'11 o 11,"1."0-SP-0-oP-0-oP--0 NyLir -' i NI-12 1 1 O i 1 II HN õ..N H2N 0 1 t 1 OH OH OH ' "/ N, N
HNõ, _...-N OH H OH .," N, N y HO d Ome --r HO = 0 '10Me .""1 'P,-N¨ / d 0 o/ 0 N¨
/
r--\r \ir NH
Hd - N., NH
Hd1 ' 0 OH OH i Compound 426 Compound 427 Date Regue/Date Received 2023-07-07 \ \+ N-Th 1,-.--,N
11 + N.---=\ F.---N
gy.-^1yN", , , 041 -0 -Ov0 -OA-0,....-co,... Nõ,.õ,N112 N N,,, ,,,0-9-0-6&-0-9&-0,.....Ø.. N v i NH2 HN , N OH OH OH
HN ...,- N OH 01-1 OH -- , HO d bme --' --,- HO d. b Me ""---0. , H2N 0 H2N 0 ''' P,- N¨ cl , 0 N¨ 0 /

-- \r )r.NH
HO' HO' -N.2..i.,,NH
' --Compound 428 Compound 429 \ \+ N.,,,-- \ f=N
+N=A f=N N 0 0 0 S 0 N NH2 0 H2 O N - - '. oAoAolgo--"(r y o---YN''. O ''''o-ig-o-A-o-FLo , , , ----NY)''YN HIi.j:: OH OH OH
HN - N OH OH OH N y HO 0 ,112_ 0 M e "r- HO d bme ----' H2N 0 'P...- N¨ c5 o 0, 0 N¨ /
/ rl',I ,0 \....Ø..Nr---Nro Li¨ ,-rNH
HO' -..
OH NyNH
HO'. '.-... 0 uH NH2 Compound 430 Compound 431 \
\ -,N=\ ,,----N
+ N=\ n¨N 0 0 0 6 0 'õ?..iNH2 N Ni÷. t) 'no4A-A-o-ig.--o oN". CI FL-0-(1:11--0-Fl-e.'"'(_"'" .7 i i HN, .....-- N OH OH OH
HN - N OH OH OH N , N T HO
HO ci bme , 0 N¨ 0 / N
/ N P
====C, ).... -N-?-õr r=t:...N \r 'OH
FICS' '' N y NH
.L.-/
HO' i....
uH 9 NH2 Compound 432 Compound 433 \ \.N=.-_,, 0 f="

+ N= \
0 0 0 F.---N
OY--.'N''. O ..`04-0-1g4 4-0 o.--..'"1"42rN"' Ci ''''O-A-A-A-O-A-(3,---cor Ny)---rINH2 i i , i HN,N OH OH OH N N HN ..... N OH OH OH
T HO 0 'OMe .......,'' --,- HO
0.. /
0... / H2N 0 H2N 0 N¨ 0' N¨ 0' CI / 1=N N
/ \.,..,õc0,_ 0 \r,,c_0_,.N --r-r9 I-16' ' 0H N1 , NH

Compound 434 Compound 435 \ \
+ N:=.- /-.2=N +N=\ ,/=N

0 i\J , , 9 9 H 9 0 N NH2 0 0 N
N N" ''''o-i:,t o A o A o o^
C..Ø... µi7Lell2 ..---4.'''',,r 1 . ' ' '''.01-0-F,'-N-P-C;(**-c )--- Y----;c-i Hitii... OH OH OH OH .."- N , N
HN ....- N OH OH OH .2' , N ..... N T HO 0 bkie --, )-- HO 0 ome ---""
/
H2N o= 0. `P.,- N¨ ci 0 N¨ 0' H2N 0 / ire--N
..,,õ(0)....N y,...ro /
\*.,r0NrfNH r.9 OH
HO' '2 N , NH
;1---...
HO' " 0 Compound 436 Compound 437 Date Regue/Date Received 2023-07-07 r_-_N, i NH2 ON.z...-4,7õ, ,+\:4:\N'. O ''..O-LOI-CH2-L-Clo:(3:4 '173thAreYNN'..----' NNH, \
*N=\

(:)."---YN"' '''.0-0111-0-0P-O-OP-0-0P-0-a*"-G.. N'Y'''''1' HN .....N OH OH OH OH - -= N N Y HO
y HO d Ome -'''''=
o, , H2N 0 H2N 0 N¨

N¨ 0 /
/ \ 4..0, N/7 o \''C.N0 *trNH OH
N:.=,,,c, NH
bH 9 NH2 Compound 438 Compound 439 \ 41 +N--,-- \ T=N , ----r\ r-,-N
.0 0 0 0 0 c12 0 0 0 C)N''' ',"0 111 0 112, 0 0 0 b.2 A o A-0 0 ,,,,,.....ryii2 (31'1'' ''''0 l',, 0 I', HN,N OH OH OH OH " , N.õ N HN .,, N
OH OH OH OH , ' N, N
-7- HO 0 OMe r Ho 0,5i bm. --,.
0, , ...,:s H2N 0 N¨ 0 N¨

, 0 /
"*"1.3...('O
=ir-NH
H HO' - N , NH
OH 1d 1...
oH NH2 Compound 440 Compound 441 \
\ -, N.-=-\
0 0 0 ir-=-N
Q N'' ) ) 0 Ol--'YN''. ''''o--o--ig-o-&-c,"-0-==0 Ni%-"rNH2 0 il 11' 0 14:'=:. 0 N1 H N2 ' 14 OH OH OH N N
HN,N OH OH OH OH , ' N., T HO N-11 b M e r HO 7 6 brine H2N o o, , H2N
N¨ 0 / 0 r=" / _.N ..õ \=-0...N0 .. .
Hd HO' ' 0 OH - OH y Compound 442 Compound 443 \ \.N..¨ \ f=N 1 -,-N=\ F.--,N 0 0 0 0 0. ssi,yilõ,(C) õ,,,,.. 9 9 9 13 N ""' -""-o-A-o-ig-o-Vo HNõN OH OH OH z , N
IN
6,_, 6,_, (,),, = ., N , N r HO d bime"-'-' T HO NH Lime ---" o, , o. , H2N o -P,-H2N 0 N¨ 6 o N¨ 0 / /N
/
\rr \'`,C
),,,.N.,,,,,,,,,,r0 \r-NH
Hd ' N , NH
OH y bH

Compound 444 Compound 445 \ \+N-Th f= N
11 + N= \ r=N 0 0 0 N
,C)4_0_. 1 (3Ovo.....\, )...Nõ,,rI'''',."'(N"'-o-ig-o-A-o^-0-=
i HN, _...-N OH OH OH HN,_,....-N
r HO 0 OH OH -", N N
, dbivie "----' r HO d bMe H2N 0 ( H2N 0 N¨ 0 / 0 N ¨ 0 /
/
r µ......c.....N0 NtrNH
Hd ;:._ u N, NH
- -HO' "
0H 9 H y Compound 446 Compound 447 Date Regue/Date Received 2023-07-07 \ \+N=µ F--N
r.----N 0 0 0 0 9 9 9 0 H2 1), N
"=5' .'"'''O-1-O-c.-Ol-O N Nõ, ..õ,0+04-04-0,.....0,0 HN ..,.. N 0 OH OH N N
HN ....- N 0 OH OH -- , N .... N y HO ' oMe "'"--r yHO d bMe '''-r.
H2N 0 ( H2N 0 N¨ HN
N¨ 0 /
/

\r-NH
s. .HO bH N y NH
HO' - 0 Compound 448 Compound 449 \ \
-,- N=-\ f=-N 0 .õN 91 _7 9_ 'co_1"

(:)'''Y N ''' '014-0-IL-0-A-0'.."0" 7 i 1 HN ..- N OH OH OH .." ' N N
HN - N O OH OH 4:. .-omeNzk.,N sr HO 0 OEt y HO
H2N 0 >C' H2N 0 N¨ HN / /
\ N
*....,c7y...rc, C yNNr'C) 7 rNH
' .õ NH
.. .
H0 HO' N -bH 0 OH 'r Compound 450 Compound 451 \
\ +N-==1, r---N
+ N.= \ /=N 0 0 0 0y,crN 0 O-F,,-(4-0-9P-0,,,,,,c ,r,N 0.ygsyw, 0 ,,No-p-4,2-4112_41 0 /7 P!' /7.

HN , N OH OH OH
HN ...- N y. HO 0 On-Pr y HO OH 6H OH d"-bEt N''''''N
0.
H2N 0 ' P, H2N 0 ' P, - N
N¨ 0' 9 /
/
cOy..r\r \****.-C.....NN.....0 NH
HO'.. ' N ..õ NH
HO' ''.:- uH bH 'r Compound 452 Compound 453 \
\ +N=\
-,- N=\ /=N 0 tsj 0 0 0 0 0 f=N NH2 ONõ, O o1LO-FLO-;Lo.."-'0-P-0-1LO-P-ON
i HN õ.. N
HN ,,N OH OH OH -" , N N y HO 0H OH OH 6- ,proNN
Y. HO 0,p,:d.:. 'Orr-Pr ''' H2N 0 N¨ (5 0 N ¨ 0' /
/
CO-.1\r--.-\C) Z
sir-NH .
HO' ,oH NI ...iNH
.'----HO' ,(5Fi 0 Compound 454 Compound 455 \
\ *N=\ r.---N
+ N=\ N oyy N õ .5 O , , , % ,õ 9 9 9 0 N
õ?....,,T, NH2 0,....õ..(y N õ --) , ,o,..õ0 _iii:i_ olL 0 _FL 0 f'0 F,' 0 F,' 0 ..." - - - - - -i HN ....- N OH OH OH -", HNõ_.,.. N OH OH OH ' .,õ..õ. 'sr HO d -on-Bu r HO d bi-P, o. /
H2N o -P,-H2N 0 "P,- N
N ¨ 0 NrNH
' ' =.õ NH
HO' -;.-, u H 0 NH bH
i Compound 456 Compound 457 Date Regue/Date Received 2023-07-07 \
N=\ r=N +N=\ n-N

0,,i,N,.. 0 ..õ,,o-ovo-ovo-011L0,,t,-0 N .N.?..õNH2 N OPOPOPOo I
Ny)õ,õirNH2 HN --N - OH OH OH - - N N HN ,N
Y HO d -On-Eiu '-r y HO
H 2 N 0 F, 0.,../..

/.... 0 N- OH OH OH 066 ",..0Me N-'---/N
N¨ 0 0 /
/ 0 T=N
\..õ,c0i....r\nr 0 ,ti-NH
HO' - N, NH
HO' " 0 bH OH `r Compound 458 Compound 459 .N...--\
0 0 0 1=N +N=\ /='N
O ,5 FLO-FLO-FLorNm12 0.yyõ. 0 ...,,,o 11 ....-0-Org...Ø...Ova,.....0,. NH2 HN,N OH OH OH ' , N ,õ. N HNõN OH OH OH
" , N, N
r HO 0: bivie HO 0, ,c5" -0Me '''''' 0,r,/,..._ H2N 0 -1.õ-N-/ /
o\...._(0\..r\r \.5,...Nr-N 0 ..),....NH ,. , ..\---/ = N,zyNH
HO
' bH O HO' oi-i Compound 460 Compound 461 P
-,-N,,\ +N=r\ F=N

0.,),--õNõ. ..,-,o_F,I,...04_01..0 /=N
._,..,0,Ny..\-.õ1,7 NH2 0y,,. (--) .,, 0 NH2 I µo-A-o-11-o-ig-o , , , HN -N OH OH OH -" HN,N OH OH OH -". N, N
y HO di OlMe ""--/' T HO ti oMe 0õ,,,,,,_ 0, /

/ / 0 ir=-N
C'C'N\rC) \4===--Cy, s= .
HO bH o HO" -13H N.,y. NH
' Compound 462 Compound 463 P \
0 0 0 irr'N
P-o-A-o-ANH2 ~ N.",-"A

HN, __.--N I
OH OH OH " , N, N
0 N _ NH2 O LO-FLO-P-0 T HO ci -0Me I 0õ,.., _ õ..NH 0 HN ..-N OH OH OH ' ' N , N

Y HO 0 OIVIe 0 / / 0,p0 ,...
/
\....,cly..) Nici\j H2N 0 o N- ..."
/ \....,c7"...r.-\r0 HO" ' N1-,.
NH
-OH y \11.-NH

Hd bH 0 Compound 464 Compound 465 Date Regue/Date Received 2023-07-07 \
0,,, N,,, 0 .,,,,,0-0A-0-0v0-04-0,,......cr \ +N=\
+N....-r.-\
0yzyN,,s0 0-0A-0-04-0-0A-0,......c0)....Nr?N NH2 o I HN, _......- N 1 t 1 I
OH OH OH z --HN ...- N OH OH OH z -- N -.... N T HO d blue ....r HO d oMe /
Nr..NH 0 r- NH 0 "P,- N¨ 6 o I /N¨ O / f----N
\*.õc.....0 N e HO' HCf ' N,.. NH
' - bH i -bH NH2 Compound 466 Compound 467 \
=N 0 r..=N

-,N=\ / H .y.y,,. (3 .õI 11 11 11 N Nrk,i, N FI2 0 0 0 -Fi'-o-i7 -0 -1:'-'0..."-(71'. 7 O.YCrN" CI 1 1 1 1 HN ..-N OH OH OH N
HN õN OH OH OH " ' N.,. N sy HO
HO 0, p'' bivie ---/
H2N 0 0,45_ bme -'' N¨ 0 ( N¨ 5 0 /
/
......cC:y...ir\r 'NH
. Fid ,bivie N,TõNH

Compound 468 Compound 473 \ \+ N.=\ f=--N
+N=.\
o./syN,,f ..,,,,,.,01,1,-04-0-9F;)-0 0 /=N 0 0 0 0 N' O o-A-o-A-O-A-o."---LrNy7'.\-'iI
Y4y. i , i HN,_..,-N OH OH OH , ' HN ,N OH OH OH z , NI, N T HO
'sr- HO 0, /
0,p!_ .bMe H2N o H2N 0 N¨ 6 0 N¨ 0 /
/ r 0 /=N
NIT-NH ,...- .
HO -..._ N,NH
.-1----/ On-Pr --f HO `
bMea NH2 Compound 474 Compound 475 \ \+N=\ /..¨N
0 0 0 fr---.N 0 0 0 Y.-Cr'N"' O ''0-1L0-11-04-0 Y-4NrN N)' ''''''O-P-04-04-0---cor N ,,,.?-iiNH2 , , , i HN ....-N OH OH OH "= N.... N
HN ....-N OH OH OH z ' NI, N --r H, eH2 bme -------,-- HO 0 OMe "=-='" 0, / _ 0, / H2N o H2N 0 N--"" 0/
, 0 N¨ 0 /
/
\\C_.y..:21 Ni::::
."
r NH
HO. ' N , NH
- bH 1 H0µ -on p9 Compound 476 Compound 477 \ \+N=\ r.----N

+N--=\
0 0 0 ./.-.--N
,--tyN,,. õ,, 11 0 0,õ....yN,,.5 ...,,...04_04_o_ig_07,..N ..N ..,r NH2 N, .'0-P-O-P-O-P-0.4-0") i HN ..,.,N OH OH OH I
" ' N , N HN ...- N

Nr HO eH2 OMe µ`" 0, , H2N 0 µ, H2N 0 '1''.... N¨ 1-126 '-' N¨ 0 O / F.---N
/
\...,,r,r0 NH
1-15' - N, NH
,1---/
Ho' - o bH OH ---r Compound 478 Compound 479 Date Regue/Date Received 2023-07-07 \
\
N..--\
0 0 0 0 r=" oy,...crNõ, 0 õ..õ0 ' _01L
II 0 0 N,..r.)--õrNHz y-'=(*y ' o_p_o_p_o_p_.---c ry---,- HN õ-N 0 OH
OH
HN --N OH OH 0H - ' N N y HO -)-- HO d bivie 0.,p/.õ_ / 0 N¨ 0 r--.--N
N¨ H /
.20 /
\,....,c0i...r..\e NH
HO" - N,,, NH
HO' , 0 bH y OH

Compound 480 Compound 481 \ \
o m .,/ 71;\,),,NH2 'N¨\ 0 0 0 0 /=N\
H2 Oy-lc+ N, ,õ, 9 9 9 (:)`y-jrNi''' HN ..--N 5 3 0 OH OH -. ' N.,õ N HN , N
--,-- HO bMe '''-'/ y HO OH OH OH 0, p .-,OMeNN
H2N 0 ( NH Me0 N¨ 0 1 0 /
HO'* 0 uH HO
s :0F1 Compound 482 Compound 524 \
-,N=\
0 0 0 /--,--N \
+N---,---\ r----N

C)--.N../"µe." 0-11,1-0-12.-0-FLO'OrYIN
1 13Y-YN." 41-0-41-04-0 NNH2 HN ---N OH OH OH ; , N,õ, N
y HO HN,N
T HO OH QH OH d' H2N C! `ow ----'' 6 OH H2N --P, o/ OH
0 \....,(0j...Nf=1:0 N¨ V 0 / N¨ =,11.-NH
N, NH /
bH y HO' , 0 OH

Compound 539 Compound 540 \
\
o oõy,y+N=V, 0 .,õ,Li_oiNr,?,iN... 1 NH, +N=\
Qrc,r, N,õ 0 i _01!_oõ...-co,r.N,?-.õ1,NH2 HN,N OH H H ; , NI, N 1 1 1 T- HO d bMe ' HN --N OH OH OH -- '-N
0_,s,0 0, HN, / -1- HO c! bMe Y
H2N -P, 6 OH H2N 0.-:-.'.s, \ HN-o \.....c.:51 ,Nr-r)1j ro \
V
sir-NH
HO'' ' N , NH
bH y HO)-----/
, 0 OH
NH, Compound 541 Compound 542 \
*N=\ -r=N \
+N-,---1, r---N
.õO-F,._.:,,?-01-. 0 Ny,H,,NH2 , 0 0 0 0 m NH2 HN --N Ei H3 (SH (SH 0 bime N N
HO HN --N I:13H OH OH
t) _ 3 0 bMe Y
, o '-' ..µr- HO
H2N Me .13., d OH H2N Me0 o/ OH
ri\NO
V
)1-NH
=,. H N.,, NH
I
bH 9 Compound 543 Compound 544 Date Regue/Date Received 2023-07-07 \
\
+N=\ f=N 0 4_01.01_0õ......O... +N..=\

rY'yr i HN ..õ.N OH OH OH 0 N, N
y HO 6 OMe .--' HN HO , _--N OH OH OH --, N N
, T
H2N Me0 -0 Me ci H2N Me0 0, 0 V
õ. orNH
HO' ' '-oH NyNH
HO' OH

Compound 545 Compound 546 \
-,N=\ r--N \
O '''0 lg S:
0 F' 0 s 0 N y7iNH2 "I-N=\ f=N
..õ...,01_01t,.,\.-0,,NNH2 HN.,_--N OH OH OH , , N, T HO d bMe `='' HN, õN HO OH OH OH
Ci bMe `s"
H2N Me0 `P,,..,-O - H2N Me0 N?.,{ 0 V
rNH
HO' -.._ N,NH
oFI I HO' . .bH

Compound 547 Compound 548 \
+N-=-\ /-=-N \
N,,,c N ,, 0 i J_04(:)...0 0 N NH2 , 0 0 0 0 HN,,,, T iN OH OH OH {
HO 0. bMe HN, ,,,N OH OH OH
0,,,./ T HO 0- oMe '-"
H2N Me0 '70 H2N Me0 HN HN'70 Z
HO' .b1-1 NyNH sirNH
HO bii 0 Compound 549 Compound 550 "
-,N..¨\ i=rs, \
0 47_04_0 +,,,,==\
,....õ(_.)..00 N NH2 . 0 .
. 0 , HNN OH OH OH ' , N, N
T Ho HNN OH OH OH
0, /0112 bMe T HO
.*CD
HN 0,,,s/bSH2 "b11/1e N '' H2N Me0 N

N -7 H2N Me0 H0 0 HO'' '131-I Nõ),NH r.NH
HO' - 0 Compound 551 Compound 552 \
-,N=\ 1=N \
0 0 0 0 0 +N=\ /=N
0 0 0 N, NH2 .)."'N''' ''''`-o-A-o-A-o-A-o"--0.= ?--ir N N
NT OH OH OH õ........\--5,õ?..õõrFI2 HN OH OH OH , N
õ1 _,N HO
- HN, _..... N s,,p(2',_ OW ''''N ' T HO
H2N meo d 0 H2N WO C...fi "bMeN''----"N
0, 0 y)...N0 0 V
..L----(.
HO' .;_._ N,NH r-NH
0H i HO' -- 0 Compound 553 Compound 554 Date Regue/Date Received 2023-07-07 \ \
+ N=.\ 0 r- ---.-- ---+ N \
0 0 0 0 0 0 0 0 ra-)--NI-12 'YN ''' '''''Cl---kL.0 (3 0'µ " o-A-o-A-o-ig-o--"--( r'N.trN
HN -N OH OH OH H71---.121): ../ OH OH OH
)--- HO ci " OMe y HO ci OMe H2N Me0 'P,- H2N Med ...Ne \,..õ,(3....N0 Hd - N , NH HO' = N , NH
bH y bH ----r Compound 555 Compound 556 \
+ N=\ /=N \
+N=3, o 0 0 0 P P
CI O-O-O-0.-OP-0 0 0 .'"04-0-1g-O-P-O'''`c '''),"\---1"..- i HNN BH3 OH OH , , N , N
T HO b bMe "----' HN, _..... N BH OH OH
_ 3 0, / T HO
H2N AcHN ""P, 0, , d OH H2N AcHN

V
Hd - Nõ .õ..... NH
oH NH2 bH0 Compound 557 Compound 558 \
+Nr----,\
0 0 0 0 /.-,.-N \
0 11 11 11 N NH2 -- +N=\

).)1"' 0,)..õc N OH OH OH ,,.' , e ,,,.., 0 " ohne NI-HN,N OH OH OH
T HO 0 bMe -----' HN -- N , N
0, / )--- H01"--"" 0 - ----H2N AcHN
6 o H2N AcHN
d 0 µ....,c0i...Nrco Ho ...-)r-NH
,,t....NH
bH bil Compound 559 Compound 560 \
4.N.,-----\ r----N \
+N=\ r=N
0 ,,,..01?_oii:pLs N y),.,õõT,NI=12 0 0 0 0 ''''04-0-1g-0-1Ls o Nõõ?....õ(NH2 HN,..,..N OH OH OH (j, '..bmeN - N
T HO H'1:2Nr 41 __ s?..õ) OH OH OH -'-....-0 l'=ome N --,,IN
y HO
H2N AcHN 'P.,- 0, , 6 o H2N AcHN ' --õNr---0 V
Hd ' N ,.. NH
bH y HO' ' 0 bH

Compound 561 Compound 562 \
+N---\
0 0 0 0 l,f=N \
+ N.,=\ i=N
,,õ 11 11 11 NH2 0 N,,.
O .õ,,O-OP11-0-OP11-0-OP11 -0,...,_corNNH2 HN -- N OH OH OH , , N , N I
)--- HO d 'mile .'-'" HT.i):: OH OH OH N
, N
0,/ y HO 0 oMe "`"=".
H2N AcHN
HN
',"0 H2N AcHN
HN
..N0 -,"
,ir-NH
HO' - N ,... NH
bH ---r- H, -,,, 0 Compound 563 Compound 564 Date Regue/Date Received 2023-07-07 \
+N=\
0 0 0 0 /=N \
,, ti 11 11 NH2 +N=\
õ,õ i--N\
' 0-P-O-P-O-P-ON'?'"Ir 0,yõcreNõ,5,0 0-OA-0-Olg_0_OA-0,0,.,7...NNH2 HN ...-N OH OH OH = , N,._ N V"
I
HO C-H2 bme "----." HN, _...-N OH OH OH -,,_ N-..., N
T HO 0112 OMe ---="-H2N AcHN 0 0-/
HN H2N AcHN O
HN
O,Nr:1\iõLro 0 tdr-r .."
Hd ' N, NH
OH y HO' " 0 OH

Compound 565 Compound 566 \
r----N \
o 0 () 0 ()it; 0 (Dig .
0 NyAõyNH, 9y.õ..yN,,. 0 .õ,..õ0 -it 01,-0 13_0õ....õ \.. ,7,...N N H2 HNõ .õ...-N OH OH OH , , N, N I I I

r HO d oMe `-' HN ,N OH OH OH , , N.,, N
H2N AcHN s,,,p!,_ sr HO
0 0 H2N AcHN d_ 'Me d o Nev Hd - N,NH
'di 1 bH

Compound 567 Compound 568 \ \
+N=\ +N=µ, -inõ,-NFI
NI 0 0 0 0 0 m -"-r-ro N , , 5 , õ 1....., I I
I I I I
.µ"--o-V=o-A-o-P

0-P-O-P-O-P-ONyN
HN ...-N OH OH OH =HN ,N OH OH OH - ', 0 y HO O bMe y HO d OMe H2N AcHN H2N AcHN
6 o 6 o cipi...Ne v v HO'' .OH Ny, NH
OH

Compound 569 Compound 570 \ \
+N
i r---N , 0 0 0 C)'',),N''' - '''''-04-04-0-P-0 0 NNH2 0 0 9 HN -- N BH OH OH ", N , N
_ 3 I I I 1 )--- HO cf bMe "---"" HN,N BH OH OH
_ 3 Z ' N N
0,p, T HO 9 bme ---,---H2N o , OH H2N 0 N¨ 0 / N¨ d OH
\/7\ro 0 r"-=\.r.0 V
N / -,,y,NH \****"Cy'rlsirNH
OH
HO' --0H 0 Compound 571 Compound 572 \
+N=\ /=N \
0 0 0 0 H2 0 + N'1., 0 9 , 9 0 1=N NH
N,, 0 ()^'-'Y ' S-1-0-1g-0-1g-0 r NN
HN õN OH OH OH - - N-... N \ N - = S-P-O-P-0-P-0 r N 2 sr HO d. --0Me "'"----- HN ,N OH OH OH --0,p/, .. Y HO

N¨

/ N¨ O
\"^-,c3,Nr-to /
v ,ir-NH
Hd --_, NI_ ,-,õ NH
uH 1 H9 "bil 0 Compound 573 Compound 574 Date Regue/Date Received 2023-07-07 \
+N=A 1=N \
0 =0 0 0 õ,o_ig_o_vo_A_sb.. N2 1 (:)Nõ,5-0 111,1_01Ls,¨..co-,7....NirNH2 HN -- N OH OH OH -"- N
--,- HO d bMe -----"" HN --N OH OH OH -- , N -..., N
O. / --,-- HO Ci bme '--HA o N¨ ci H2N o -P,-, 0 / N¨ 0 /
7.
Hd .-i3H N,õ,r, ,NH
HO' ' 0 OH

Compound 575 Compound 576 \
+N==\ ../.-=N \
(11.1 ' 0 IP? 0 (11"") 0 0 1 Nõ. 0 .õ,..,0131 g _0T o .0,..._crNNH2 HN .õN 1 1 1 1 )--- HO OH OH OH (3.' --oMe NN
HN N OH OH OH -- , N ..õ N
O. / Nr HO O -me H2N 0 `p,o N¨ HN H2N 0 HN '0 / N¨

\3,..N7NO /
,.
N

bH -....y.,NH
Ht OH

Compound 577 Compound 578 \
-,-N--=-\ r=-N \

0,y,..4...yNõ, 0 ,õ,õ,04_04_0....voõ......c...Ø).,fty).õ...c,NH2 HN --N OH OH OH {
= , N., N
OY'Y = A-0-P-0-1'o_r y HO C.H2 bMe HN, ...,N OH OH OH .: NN
0,,,..,/ y HO

HN/"0 N¨ H2N 0 cl,,CH2 OMe '7"'"..0 / N¨ HN
\i=Nv ,0 / 0 tr\C) Nr`f \*i_yrNH
HO'' ' N., NH
OH -...r HO' "
bH

Compound 579 Compound 580 \ \
+N--,--\ F--N

L041-0-P-0 O NyA.,õrNH2 0 0 Y'YN". A-o-iLo---``-0-",NH2 HN, _..... N 6H OH OH ,,, ,, N.,,,N
r HO 0 OMe HN N HO , _,...- OH OH OH ", N
d bmeN'''' N2N o H2N 0 s, /
N¨ 0 ' 0 /
\roarr\HO N OH ) H /
!,,,----f NyNH
O' ' HO' u ,.., Compound 581 Compound 582 \ \
.N.--..\ +N---.---0 0 0 0 r----s\r 0 0 0 ,,, ll 11 11 ', 0-F,'-.0-P-0-P-0 'r=NrNH ()''''YN'''5 '.."'04-0-P-04-0"'****.cosi-N \trA
I I I ft HN ,N OH OH OH HN , N OH OH OH
o )-- HO ci ) m / OMe -- HO d 'e , /
H2N 0 --Põ-- H2N 0 'P,õ-N¨ 0 N¨ 0. 0 ' 0 / \ / N0 ..,õ to....Nr--0 HO' :OH N,,,i, NH Hd bH 1 Compound 583 Compound 584 Date Regue/Date Received 2023-07-07 \
+N=\ r,--N \
0 0 0 0 + N=.-r\
0 0 0 f--,--N
4-o-A-o^(3-"NN H2 (:)õ,,,,,4), ,Nõ. 0 ,,,,o_vo_vo_vcrõ.....0,00 N ,. /.,,y NH2 HN, ____N OH OH OH I
, "- , r N N Ho d 'ow --' HN ..-N OH OH OH , , N -.., N
0- , -1--- HO 6 01Vle ' H2N 0o 6, o H2N 0 0, , HN o \*....0õNr:-.1 f O 0/ 0 \ HN 0 \
O,Nr\r--V
N yNH Ni-NH
'OH HO' - 0 NH2 bH
Compound 631 Compound 632 \ + \ +
N..\.
0 0 0 F.--N N...=\
0 0 0 0 f--,--N
OY\i''. O 2µµO A o ig o 11= o^-ONINH2 ON". P 0 P 0 114 I
HN,,,..N OH 0H OH , , N N HN,,N OH OH 61-1 NH
r HO
0, Fl Me HO 0, 6' bme y H2N `1.õ - H2N 'ID/, N
7,y0 1---) 0/
CO...N7r0 ' -HO' O -,H N bH , NH HO' - N NH
y Compound 633 Compound 634 \
-,-N---\
0 0 0 f-=-N \
0 N N õ, ,.,µ-gA_0,...-c_)... Nõ?,,(NH, +N=\

/=N
HNõ--iY.N... OH ON bH =", N -- N
T HO
0 ,..0 HNN OH OH OH
H2N N3 0 , P. orrAe -----1 T HO
O H2N N3 0,F)/6::.
\
0' ...,c0y,,,,--N--10 0 rN, , N yNH sy-NH
bH HO' u .., H

Compound 635 Compound 636 \
,-N.=\ /.--,--N \
0 c),N,.. 0 LOIL0_?,...0 r--N
Ny NI ". ."'"`o-fLo-oiLo-oA-0 N'''N H2 {
HN .õ..N OH OH OH ; , N ,, N I
y Me0 d -0Me '"-=-= HN,N OH OH OH
N
d bMe H2N Me0 'R.,- 0, /
6 o H2N Me0 V
Hd ' -0H N),. ,NH
HO' u "-._ 0 H

Compound 637 Compound 638 \
+ N=\ i-,--N \

0,y.crN, 0 , 4111 ...0,,,,....o.0 N õe\ NH2 +N--=\
0 0 0 r--N
{ 131-"--YN O 0-P-O-FLO-P -0 HNN 1 t 1 i T HO OH OH OH 0; 0me N
HNõ .......- N OH OH OH N
HO 0 oMe --"-H2N HN -P,- 0. , 6 o Si H2N HN
¨N 0 0/ 0 \'... Nr r 0 \ 0 ¨N ....-Nr.
V \ r )r-NH
Hd. ' N .õ NH
'OH y Hd "ibH 0 Compound 639 Compound 640 Date Regue/Date Received 2023-07-07 \
+ N=\
0 0 0 i=N \
-.N=\
(:).=--CrN". A-o-A-o-A-o^c_ _rY--rNH2 0 0 0 0 r="v NH2 { oN5o HN ....- N OH OH OH z ' N -.... N
y Me0 HN ....- N OH OH OH -- ' N .... N
., p OlMe ----".
."1--. Me0 d bMe H2N HN 'P.,- 0/, _ ,-,rNH
NH
Ny OH HO' - 0 bH

Compound 641 Compound 642 \
-,N=\ r--_-_N \
T=N
oy),,y, N ,,. 0 .,õ,0 L i'M: 0 0 -,N----A, N o N
y.)7iNH2 0 0 0 0 l---Y'.. ...solY, o A o A o^(7.1"NH2 y HN -- N OH OH OH , ' N .._ 'N
1 1 1 i HO (5 b M e "--". HN õ- N
OH OH OH z , N ..... N
0,pr,_ HN¨\ 6 0 6,4_ H2N o H2N 0 oMe HN---\_\_\ 0/ 0 \*...õ0....N7t0 0 V
MY OH N NH =ir-NH
HO" '0H 0 Compound 643 Compound 644 \
\
-,-N----\ /-----N
oy-&T,.., N, 0 , .....õ0_10_01_0 Ht 0 N õr.)...1,N H2 0.yy 0 0 0 N
i= k N,,. u HN, , N OH OH OH z ' N .... N
T Me;----3 HN .-- N OH OH OH -". N.,,..õ,N
0,p5:!__ Ome "-y Me0 H2N o / o H2N 0 0õ4_ bMe \'....,Cy' ..Nr"--:?0 /
,ir-NH
HO'' ' OH N .... NH
y bH

Compound 645 Compound 646 \
.N...--\ F.--N \
0 N_ NH2 + N.-..-r\
0 0 0 0 /--,N
O ."--0-i)"-0-(1L0-913-0 0Ns HN,N OH OH OH z , N ,. N 1 T HO HN, _.-- N OH OH OH _z: /- NN
0õp!._ -Me '''." T HO o OMe H2N HN 0 õ F,, _ 0' \ d õNic),,,ro c1-µsi__ 0 V
OH N,..y. NH
HO' OH

Compound 647 Compound 648 \
\
+ N=\
"
+ N.-..-. i=N
,- \

q'Y'Cr'N. ""'5 CI-OP-01-0-OP-O 0 N NH2 0 v \ '''''S'`) .."'**YyNH2 N OH OH OH N -, N
- ow1- HO d 'onne ---/ HN ...- N __ OH OH OH ' "
N .., N
. / y HO c 0 f ----7 H2N HN _ -P,- 0. , V ..sS-.
OH N..,,,,i. .NH µ17,-NH
.-\ __ /
HO' = 0 OH

Compound 649 Compound 650 Date Regue/Date Received 2023-07-07 \
+ N=---k Ý=N \
,..0 JiL01,_041Øõõ.....c0).., /=N

1 1 1 y 11 N. A, ,NH2 0 +S\I=\ 0 1.----c'yN"5 '."'""o-A-o-i=--o-A-o---c HN, ____N OH OH OH -- __ , y HO HN .õ.. N OH OH OH -- ,õ N , N
H2N HN 0 OMe ---."
y HO
H2N HN c), ;Cro OMe --'' F
\*I7l" NH ,.1 7 Ho' -.._ N õ NH ., )1 HOõ - 0 Compound 651 Compound 652 \
/=N \
oj\i0 1:_01L0 (,? 0 0 0 r----N
.. NH2 HN õN OH OH _pccH0---...cCIr N NH2 0y...,y+ N=NN,, 0 .,,,...
0-- -,0me N,...õ.õ N = = 0 -1"1-0-PH -0-Pn -0..'..-co)--.'"),)---r7 1 Nr- HO HN , N OH OH OH -- , N,õ
N
0õp/,_ y HO O 'OMe H2N HN 0 0,p/.,_ id 0 H2N HN
.'-.CC,.5...N0 :S--43 c5 0 y7 T o- \.......\\
\,..õ,,(0....... rNr Fid - N , NH
y )1-NH
OH HOõ L---/_ -Compound 653 Compound 654 \
-.-N=\ p=N \
0 0 0 0 0 0 +N=1, ÷ NH, 43 2....õ1rNH2 C)..)..,,N,,, .õ,,0_A, ,_0,.....N i HN , N OH OH OH , , N , IN
y HO
0, O' OMe --' HN , N 0 0 0 OH OH OH -÷- N, N
Y HO
H2N oo 0 o H2No HN
HC
,r-r-NYNH HN \,......cir 0.".. 0 r O NH
OH HO' ,. 0 NH, H
Compound 655 Compound 656 \ \
-,-Nr=.\ +N=\
0 0 0 0 0 F=N NH, 0 0 0 c)µ" '''1),, NI' .'"``o+o-kiLo+o--"0"N),,,)`y Q.Y.S"'N'''5 ''''''O-P-0-1g-0-A-0 0 Ny,H,õNH2 HN ,N OH OH OH , , N , N HN , N OH OH
bMe ---' y bMe HO 0. .---""
0, /
H2N C)to -P,- H2N 0 ' F),-1-11si 6 0 HN
N/-1,¨.0 \..y.o)...rNH
r r T
HO'. .",.. N ,y NEI
uH
HO' t...J ,.,H 0 Compound 657 Compound 658 \ \
-..N.---,--N /=N +N:=\ r--N

N ,,,, it 11 11 0 (D'Y'Cr. " 0-p-O-p-0-p-e--0-.NN?'Ir NH, oy-Cr-N-5 ---04-04-.4_.
HN õN OH OH OH " ' N , N HN , N I I
OH OH
)--- Ho ,,_ O' .-0Me "--"- -7--- HO di' OMe '-' H2N o H2N o HN ic,i 0 \,....,coyirN .,0 HN
\......c0,tir-Nr (-3 -1 NH
t34 6 strNH
HO' ' 0 -OH
NH, Compound 659 Compound 660 Date Regue/Date Received 2023-07-07 \
+N=\ 1=N \
0y, ,..y N , , . O 0 1,:).._ 0 1::),!. - 0 IL 0 N N,,,,, N H 2 +N=\

1 0 I N ,.5 ,1s;...,õ,041 ¨0¨ Vo¨pll ¨(:).
^Nrary7),,,rN NH2 HN ....- N OH OH OH -"- N
y HO d bivie HN - N OH OH OH -- , N , N
0. / y HO ci Ome --' H2N HN =-P,- c), , o 6 o H2N HN

0,) c..),,,,,ro (\ H0'.
.bH ., N y NH
C., HO' bH

Compound 661 Compound 662 \ \
-,N=-\ T=N

O.,,..-4,1,i,,, Ni,. 1,? 0 (113 0 C:i 0 N NH2 0.4õ,,,,,,,, N''.c ..µ"0-P-0-11t0-P-0 NNH2 HN ..- N OH OH 0H {
- - N , N HNI fl 4,/ '',47 OH OH OFI -- , N , N
--,-- HO 0... bme ----"" )----- HO b onne ---' c), , H2N HN 'P,.- H2N HN
o 6 o 0 ci 0 HO' N NH
NTO
r---\----Z. ., - ..õ
bH y Z
HO' ' 0 OH
Compound 663 Compound 664 \ \
* N=A r=-N +N=µ, r=N

0 o 11 A_0,....0,0 NH2 o ,..., NI, ,.õt;_o_i_o_ig_o_-__0.-yõ,(NH2 =

HN ..., N OH OH OH ="- N , N HN , N , OH
OH OH .: N , N
y HO (5 'me 0, / '' .`r HO 0.` 'OMe "---...
0, /

6 o d -o Nr=1:0 o ,coy.Nr-,0 c3 oH 7 N yNH
Hµ.
'bH

Compound 665 Compound 666 \
*NI= \
0 0 0 0 r----N \
L v 0õtõ.../..y N 0,, O , . 0,,04_0_,o_oõ,0.... N ..i.;.,...),y N H2 0 yy ,,, ,o-tiLo...toi-o,...4,..C)....NT,NF'12 HN .., N OH OH OH ,,,. ' y HO c5 oime '---' HN ,,..= N OH OH OH
= ' N .. , N
0, , -,-- HO 0 <We H2N HN -Põ,- 0, /
0 6 o H2N HN

HN
\ HN
V \
)= (NH
HO' ' =;, N yNH
OH bH

Compound 667 Compound 668 \
\
+ N=A r.---N
/=--N

4-0-P-O-P-Oca'rN'?'YN
V

HN ...,N OH OH OH ' ' N , N HN
OH OH OH ' =-, N , N
Nr- HO OMe '---""
0 , O OM e ,,,:..N .."---"- r HO d , H2N HN 1=',- H2N HN 0. == I.,-0 6 o HN
Nr- f. HN
N o r--r HOHHH
:1---./.
HO' `
bH or N H

Compound 669 Compound 670 Date Regue/Date Received 2023-07-07 \ \

=NN=\ $__ C4-4-0;- '-'s-C'rd=r;NH2 HN,r,_ N OH OH OH - = N --, N
y HO
Nis 1 HO

HN
N
N/=-0 ( 6 _oh, , _-).,,,NH 3 OH )01 Compound 671 Compound 672

18. Use of the compound of any one of claims 1 to 17, in the manufacture of a co-transcription reagent for RNA capping in vitro.

19. An RNA molecule, comprising the compound of any one of claims 1 to 17, as a cap structure or a cap stmcture fragment.

20. A pharmaceutical composition, comprising the RNA molecule of claim 19, and a pharmaceutically acceptable carrier.

21. A method of synthesizing an RNA molecule, comprising steps of:
co-incubating the compound of any one of claims 1 to 17 and polynucleotide template, and transcribing the template.

22. A transcription reaction system for RNA capping, comprising polynucleotide template, the compound of any one of claims 1 to 17, NTPs, and RNA
polymerases.

Date Reçue/Date Received 2023-07-07